Structural and functional brain alterations in a murine model of angiotensin II-induced hypertension. J Neurochem ; : — Banks WA.

Blood—brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des ; 11 : — McColl BW , Rothwell NJ , Allan SM. Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci ; 28 : — Hirooka Y. Sympathetic activation in hypertension: Importance of the central nervous system.

Am J Hypertens ; 33 : — Obari D , Ozcelik S , Girouard H , Hamel E. Cognitive dysfunction and dementia in animal models of hypertension.

In Girouard H ed , Hypertension and the Brain as an End-Organ Target. Springer : New York , , pp 71 — Google Preview. Zicha J , Kunes J.

Ontogenetic aspects of hypertension development: analysis in the rat. Physiol Rev ; 79 : — Tayebati SK , Tomassoni D , Amenta F. Neuroinflammatory markers in spontaneously hypertensive rat brain: an immunohistochemical study. CNS Neurol Disord Drug Targets ; 15 : — Inflammation of different tissues in spontaneously hypertensive rats.

Sheng Li Xue Bao ; 58 : — Tomassoni D , Avola R , Di Tullio MA , Sabbatini M , Vitaioli L , Amenta F. Increased expression of glial fibrillary acidic protein in the brain of spontaneously hypertensive rats. Clin Exp Hypertens ; 26 : — Waki H , Gouraud SS , Maeda M , Raizada MK , Paton JF.

Contributions of vascular inflammation in the brainstem for neurogenic hypertension. Respir Physiol Neurobiol ; : — Sabbatini M , Catalani A , Consoli C , Marletta N , Tomassoni D , Avola R.

The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia? Mech Ageing Dev ; : — Chiba T , Itoh T , Tabuchi M , Nakazawa T , Satou T. Interleukin-1β accelerates the onset of stroke in stroke-prone spontaneously hypertensive rats.

Mediators Inflamm ; : Gelderblom M , Weymar A , Bernreuther C , Velden J , Arunachalam P , Steinbach K , Orthey E , Arumugam TV , Leypoldt F , Simova O , Thom V , Friese MA , Prinz I , Hölscher C , Glatzel M , Korn T , Gerloff C , Tolosa E , Magnus T.

Neutralization of the IL axis diminishes neutrophil invasion and protects from ischemic stroke. Blood ; : — Saleh MA , Norlander AE , Madhur MS. Inhibition of interleukin A but not interleukinF signaling lowers blood pressure and reduces end-organ inflammation in angiotensin II-induced hypertension.

JACC Basic Transl Sci ; 1 : — Lockshin B , Balagula Y , Merola JF. Interleukin 17, inflammation, and cardiovascular risk in patients with psoriasis. J Am Acad Dermatol ; 79 : — Chronically infused angiotensin II induces depressive-like behavior via microglia activation.

Sci Rep ; 10 : Age-related changes in hypertensive brain damage in the hippocampi of spontaneously hypertensive rats. Mol Med Rep ; 13 : — Kaiser D , Weise G , Möller K , Scheibe J , Pösel C , Baasch S , Gawlitza M , Lobsien D , Diederich K , Minnerup J , Kranz A , Boltze J , Wagner DC.

Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease.

Acta Neuropathol Commun ; 2 : Ando H , Zhou J , Macova M , Imboden H , Saavedra JM. Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats.

Stroke ; 35 : — Santisteban MM , Ahmari N , Carvajal JM , Zingler MB , Qi Y , Kim S , Joseph J , Garcia-Pereira F , Johnson RD , Shenoy V , Raizada MK , Zubcevic J. Involvement of bone marrow cells and neuroinflammation in hypertension.

Circ Res ; 2 : — Avolio E , Pasqua T , Di Vito A , Fazzari G , Cardillo G , Alò R , Cerra MC , Barni T , Angelone T , Canonaco M. Role of brain neuroinflammatory factors on hypertension in the spontaneously hypertensive rat. Neuroscience ; : — Möller K , Pösel C , Kranz A , Schulz I , Scheibe J , Didwischus N , Boltze J , Weise G , Wagner D-C.

Arterial hypertension aggravates innate immune responses after experimental stroke. Front Cell Neurosci ; 9 : 1 — Brocca ME , Pietranera L , Meyer M , Lima A , Roig P , de Kloet ER , De Nicola AF.

Mineralocorticoid receptor associates with pro-inflammatory bias in the hippocampus of spontaneously hypertensive rats. J Neuroendocrinol ; 29 7 : 1 — Hojná S , Kuneš J , Zicha J. Alterations of NO synthase isoforms in brain and kidney of rats with genetic and salt hypertension.

Physiol Res ; 59 : — Vaziri ND , Ni Z , Oveisi F , Trnavsky-Hobbs DL. Effect of antioxidant therapy on blood pressure and NO synthase expression in hypertensive rats. Hypertension ; 36 : — Pelisch N , Hosomi N , Ueno M , Nakano D , Hitomi H , Mogi M , Shimada K , Kobori H , Horiuchi M , Sakamoto H , Matsumoto M , Kohno M , Nishiyama A.

Blockade of AT1 receptors protects the blood—brain barrier and improves cognition in Dahl salt-sensitive hypertensive rats.

Am J Hypertens ; 24 : — Marks L , Carswell HV , Peters EE , Graham DI , Patterson J , Dominiczak AF , Macrae IM. Characterization of the microglial response to cerebral ischemia in the stroke-prone spontaneously hypertensive rat.

Hypertension ; 38 : — Xia H , Sriramula S , Chhabra KH , Lazartigues E. Brain angiotensin-converting enzyme type 2 shedding contributes to the development of neurogenic hypertension.

Circ Res ; : — Protective effects of D-Limonene against transient cerebral ischemia in stroke-prone spontaneously hypertensive rats. Exp Ther Med ; 15 : — Cheng MC , Pan TM. Prevention of hypertension-induced vascular dementia by Lactobacillus paracasei subsp. paracasei NTU fermented products.

Pharm Biol ; 55 : — Iyonaga T , Shinohara K , Mastuura T , Hirooka Y , Tsutsui H. Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation. Hypertens Res ; 43 : 99 — Abiodun OA , Ola MS.

Role of brain renin angiotensin system in neurodegeneration: an update. Saudi J Biol Sci ; 27 : — Johanson C , Stopa E , McMillan P , Roth D , Funk J , Krinke G. Toxicol Pathol ; 39 : — Saavedra JM. Brain and pituitary angiotensin.

Endocr Rev ; 13 : — Allen AM , Zhuo J , Mendelsohn FA. Localization and function of angiotensin AT1 receptors. Am J Hypertens ; 13 : 31S — 38S. Mol Med Rep ; 12 : — Biancardi VC , Stranahan AM , Krause EG , de Kloet AD , Stern JE.

Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus. Glass MJ , Huang J , Speth RC , Iadecola C , Pickel VM. Angiotensin II AT-1A receptor immunolabeling in rat medial nucleus tractus solitarius neurons: subcellular targeting and relationships with catecholamines.

Sumners C , Alleyne A , Rodríguez V , Pioquinto DJ , Ludin JA , Kar S , Winder Z , Ortiz Y , Liu M , Krause EG , de Kloet AD. Brain angiotensin type-1 and type-2 receptors: cellular locations under normal and hypertensive conditions. Hypertens Res ; 43 : — Faraco G , Sugiyama Y , Lane D , Garcia-Bonilla L , Chang H , Santisteban MM , Racchumi G , Murphy M , Van Rooijen N , Anrather J , Iadecola C.

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J Clin Invest ; : — Zhang M , Mao Y , Ramirez SH , Tuma RF , Chabrashvili T. Angiotensin II induced cerebral microvascular inflammation and increased blood—brain barrier permeability via oxidative stress.

Iulita MF , Vallerand D , Beauvillier M , Haupert N , A Ulysse C , Gagné A , Vernoux N , Duchemin S , Boily M , Tremblay MÈ , Girouard H. Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice.

J Neuroinflammation ; 15 : Capone C , Faraco G , Park L , Cao X , Davisson RL , Iadecola C. The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. Biancardi VC , Son SJ , Ahmadi S , Filosa JA , Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood—brain barrier.

Hypertension ; 63 : — Jiang E , Chapp AD , Fan Y , Larson RA , Hahka T , Huber MJ , Yan J , Chen Q-H , Shan Z. Expression of proinflammatory cytokines is upregulated in the hypothalamic paraventricular nucleus of Dahl salt-sensitive hypertensive rats.

Front Physiol ; 9 : Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation ; 53 : — Barhoumi T , Kasal DA , Li MW , Shbat L , Laurant P , Neves MF , Paradis P , Schiffrin EL.

T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. Hypertension ; 57 : — Kassan M , Galan M , Partyka M , Trebak M , Matrougui K. Arterioscler Thromb Vasc Biol ; 31 : — Kinzenbaw DA , Chu Y , Peña Silva RA , Didion SP , Faraci FM. Interleukin protects against aging-induced endothelial dysfunction.

Physiol Rep ; 1 : e Faraco G , Brea D , Garcia-Bonilla L , Wang G , Racchumi G , Chang H , Buendia I , Santisteban MM , Segarra SG , Koizumi K , Sugiyama Y , Murphy M , Voss H , Anrather J , Iadecola C. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response.

Nat Neurosci ; 21 : — Fujita M , Ando K , Nagae A , Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension.

Hypertension ; 50 : — Rodrigues SF , Granger DN. Cerebral microvascular inflammation in DOCA salt-induced hypertension: role of angiotensin II and mitochondrial superoxide. J Cereb Blood Flow Metab ; 32 2 : — Santisteban MM , Ahn SJ , Lane D , Faraco G , Garcia-Bonilla L , Racchumi G , Poon C , Schaeffer S , Segarra SG , Körbelin J , Anrather J , Iadecola C.

Endothelium-macrophage crosstalk mediates blood—brain barrier dysfunction in hypertension. Hypertension ; 76 : — Wakisaka Y , Miller JD , Chu Y , Baumbach GL , Wilson S , Faraci FM , Sigmund CD , Heistad DD.

Oxidative stress through activation of NAD P H oxidase in hypertensive mice with spontaneous intracranial hemorrhage. J Cereb Blood Flow Metab ; 28 : — Shen XZ , Li Y , Li L , Shah KH , Bernstein KE , Lyden P , Shi P. Microglia participate in neurogenic regulation of hypertension.

Hypertension Dallas, Tex: ; 66 2 : — Dinh QN , Young MJ , Evans MA , Drummond GR , Sobey CG , Chrissobolis S. Aldosterone-induced oxidative stress and inflammation in the brain are mediated by the endothelial cell mineralocorticoid receptor.

Brain Res ; : — Chrissobolis S , Drummond GR , Faraci FM , Sobey CG. Chronic aldosterone administration causes Nox2-mediated increases in reactive oxygen species production and endothelial dysfunction in the cerebral circulation.

J Hypertens ; 32 : — Merrill DC , Thompson MW , Carney CL , Granwehr BP , Schlager G , Robillard JE , Sigmund CD.

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

J Clin Invest ; 97 : — Davisson RL , Yang G , Beltz TG , Cassell MD , Johnson AK , Sigmund CD. The brain renin—angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes.

Circ Res ; 83 : — Merrill DC , Granwehr BP , Davis DR , Sigmund CD. Use of transgenic and gene-targeted mice to model the genetic basis of hypertensive disorders.

Proc Assoc Am Physicians ; : — Baumbach GL , Sigmund CD , Faraci FM. Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen. Hypertension ; 41 : 50 — Baumbach GL , Heistad DD. Cerebral circulation in chronic arterial hypertension.

Hypertension ; 12 : 89 — Laurent S , Boutouyrie P , Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension ; 45 : — Spät A , Hunyady L.

Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev ; 84 : — Han F , Ozawa H , Matsuda KI , Lu H , De Kloet ER , Kawata M. Changes in the expression of corticotrophin-releasing hormone, mineralocorticoid receptor and glucocorticoid receptor mRNAs in the hypothalamic paraventricular nucleus induced by fornix transection and adrenalectomy.

J Neuroendocrinol ; 19 : — Rigsby CS , Burch AE , Ogbi S , Pollock DM , Dorrance AM. Intact female stroke-prone hypertensive rats lack responsiveness to mineralocorticoid receptor antagonists. Am J Physiol Regul Integr Comp Physiol ; : R — R Gomez-Sanchez EP. Intracerebroventricular infusion of aldosterone induces hypertension in rats.

Endocrinology ; : — Kageyama Y , Bravo EL. Hypertensive mechanisms associated with centrally administered aldosterone in dogs.

Hypertension ; 11 : — Francis J , Beltz T , Johnson AK , Felder RB. Mineralocorticoids act centrally to regulate blood-borne tumor necrosis factor-alpha in normal rats.

Dahl LK , Heine M , Tassinari L. Role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt ingestion. Jiang E , Chapp AD , Fan Y , Larson RA , Hahka T , Huber MJ , Yan J , Chen QH , Shan Z.

Ueno Y , Mohara O , Brosnihan KB , Ferrario CM. Characteristics of hormonal and neurogenic mechanisms of deoxycorticosterone-induced hypertension.

Hypertension ; 11 : I — I Tynan RJ , Naicker S , Hinwood M , Nalivaiko E , Buller KM , Pow DV , Day TA , Walker FR. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav Immun ; 24 : — Gutkind JS , Kurihara M , Saavedra JM.

Increased angiotensin II receptors in brain nuclei of DOCA-salt hypertensive rats. Am J Physiol ; : H — H Schenk J , McNeill JH. The pathogenesis of DOCA-salt hypertension. J Pharmacol Toxicol Methods ; 27 : — Matthews KA , Katholi CR , McCreath H , Whooley MA , Williams DR , Zhu S , Markovitz JH.

Blood pressure reactivity to psychological stress predicts hypertension in the CARDIA study. Circulation ; : 74 — Marvar PJ , Vinh A , Thabet S , Lob HE , Geem D , Ressler KJ , Harrison DG. T lymphocytes and vascular inflammation contribute to stress-dependent hypertension. Biol Psychiatry ; 71 : — Chronic stress decreases cerebrovascular responses during rat hindlimb electrical stimulation.

Front Neurosci ; 9 : Behav Brain Res ; : — Wilson RS , Arnold SE , Schneider JA , Li Y , Bennett DA. Chronic distress, age-related neuropathology, and late-life dementia.

Psychosom Med ; 69 : 47 — Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun ; 16 : — Yaffe K , Lindquist K , Penninx BW , Simonsick EM , Pahor M , Kritchevsky S , Launer L , Kuller L , Rubin S , Harris T.

Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology ; 61 : 76 — Braszko JJ , Wincewicz D , Jakubów P. Candesartan prevents impairment of recall caused by repeated stress in rats.

Psychopharmacology Berl ; : — Don-Doncow N , Vanherle L , Zhang Y , Meissner A. T-cell accumulation in the hypertensive brain: a role for sphingosinephosphate-mediated chemotaxis.

Int J Mol Sci ; 20 3 : Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging ; 33 : e19 — Poulet R , Gentile MT , Vecchione C , Distaso M , Aretini A , Fratta L , Russo G , Echart C , Maffei A , De Simoni MG , Lembo G. Acute hypertension induces oxidative stress in brain tissues.

J Cereb Blood Flow Metab ; 26 : — Sadekova N , Iulita MF , Vallerand D , Muhire G , Bourmoum M , Claing A , Girouard H. Arterial stiffness induced by carotid calcification leads to cerebral gliosis mediated by oxidative stress.

J Hypertens ; 36 : — Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension Dallas, Tex: ; 60 : — Mestas J , Hughes CC.

Of mice and not men: differences between mouse and human immunology. J Immunol ; : — Daneman R. The blood—brain barrier in health and disease. Ann Neurol ; 72 : — Maktabi MA , Heistad DD , Faraci FM. Effects of central and intravascular angiotensin I and II on the choroid plexus.

Am J Physiol ; : R — R Villaseñor R , Ozmen L , Messaddeq N , Grüninger F , Loetscher H , Keller A , Betsholtz C , Freskgård PO , Collin L. Trafficking of endogenous immunoglobulins by endothelial cells at the blood—brain barrier.

Sci Rep ; 6 : Korn T , Kallies A. T cell responses in the central nervous system. Nat Rev Immunol ; 17 : — Baruch K , Deczkowska A , Rosenzweig N , Tsitsou-Kampeli A , Sharif AM , Matcovitch-Natan O , Kertser A , David E , Amit I , Schwartz M. Nat Med ; 22 : — Chodobski A , Szmydynger-Chodobska J , Johanson CE.

Angiotensin II regulates choroid plexus blood flow by interacting with the sympathetic nervous system and nitric oxide. Meningeal lymphatic vessels regulate brain tumor drainage and immunity. Cell Res ; 30 : — Mestre H , Mori Y , Nedergaard M. Trends Neurosci ; 43 : — Mestre H , Tithof J , Du T , Song W , Peng W , Sweeney AM , Olveda G , Thomas JH , Nedergaard M , Kelley DH.

Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun ; 9 : Hunt BJ , Jurd KM.

Endothelial cell activation. A central pathophysiological process. BMJ Clinical Research ed ; : — Ludewig P , Winneberger J , Magnus T. The cerebral endothelial cell as a key regulator of inflammatory processes in sterile inflammation. J Neuroimmunol ; : 38 — Zhou H , Andonegui G , Wong CH , Kubes P.

Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation.

J Neuroinflamm ; 12 : Ludewig P , Sedlacik J , Gelderblom M , Bernreuther C , Korkusuz Y , Wagener C , Gerloff C , Fiehler J , Magnus T , Horst AK. Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMPmediated blood—brain-barrier breakdown in a mouse model for ischemic stroke.

Reglero-Real N , Colom B , Bodkin JV , Nourshargh S. Endothelial cell junctional adhesion molecules: role and regulation of expression in inflammation. Arterioscler Thromb Vasc Biol ; 36 : — Pan W , Kastin AJ , Daniel J , Yu C , Baryshnikova LM , von Bartheld CS. TNFalpha trafficking in cerebral vascular endothelial cells.

J Neuroimmunol ; : 47 — Fujimoto K. Pericyte—endothelial gap junctions in developing rat cerebral capillaries: a fine structural study. Anat Rec ; : — Liu S , Agalliu D , Yu C , Fisher M. The role of pericytes in blood—brain barrier function and stroke. Curr Pharm Des ; 18 : — What is a pericyte?

J Cereb Blood Flow Metab ; 36 : — Hirunpattarasilp C , Attwell D , Freitas F. The role of pericytes in brain disorders: from the periphery to the brain. Capillary pericytes regulate cerebral blood flow in health and disease.

Nature ; : 55 — Sweeney MD , Ayyadurai S , Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci ; 19 : — Berthiaume AA , Hartmann DA , Majesky MW , Bhat NR , Shih AY. Pericyte structural remodeling in cerebrovascular health and homeostasis.

Front Aging Neurosci ; 10 : Activated microglia induce the production of reactive oxygen species and promote apoptosis of co-cultured retinal microvascular pericytes.

Graefes Arch Clin Exp Ophthalmol ; : — Al Ahmad A , Gassmann M , Ogunshola OO. Maintaining blood—brain barrier integrity: pericytes perform better than astrocytes during prolonged oxygen deprivation.

J Cell Physiol ; : — Abbott NJ , Rönnbäck L , Hansson E. Astrocyte—endothelial interactions at the blood—brain barrier. Nat Rev Neurosci ; 7 1 : 41 — Igarashi Y , Utsumi H , Chiba H , Yamada-Sasamori Y , Tobioka H , Kamimura Y , Furuuchi K , Kokai Y , Nakagawa T , Mori M , Sawada N.

Glial cell line-derived neurotrophic factor induces barrier function of endothelial cells forming the blood—brain barrier. Biochem Biophys Res Commun ; : — Heinemann U , Kaufer D , Friedman A. Blood—brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy.

Glia ; 60 : — Prat A , Biernacki K , Wosik K , Antel JP. Glial cell influence on the human blood—brain barrier. Glia ; 36 : — Lee SW , Kim WJ , Choi YK , Song HS , Son MJ , Gelman IH , Kim YJ , Kim KW. SSeCKS regulates angiogenesis and tight junction formation in blood—brain barrier.

Nat Med ; 9 : — Michinaga S , Koyama Y. Dual roles of astrocyte-derived factors in regulation of blood—brain barrier function after brain damage.

Lécuyer M-A , Kebir H , Prat A. Glial influences on BBB functions and molecular players in immune cell trafficking. Biochimica et Biophysica Acta BBA - Molecular Basis of Disease ; 3 : — Cipollini V , Anrather J , Orzi F , Iadecola C.

Th17 and cognitive impairment: Possible mechanisms of action. Front Neuroanat ; 13 : Mantle JL , Lee KH. A differentiating neural stem cell-derived astrocytic population mitigates the inflammatory effects of TNF-α and IL-6 in an iPSC-based blood—brain barrier model.

Neurobiol Dis ; : — De Silva TM , Faraci FM. In Caplan LR , Biller J , Leary MC , Lo EH, Thomas AJ , Yenari M , et al. eds , Primer on Cerebrovascular Diseases, 2nd edn. Academic Press : San Diego , , pp — Sokolova IA , Manukhina EB , Blinkov SM , Koshelev VB , Pinelis VG , Rodionov IM.

Rarefication of the arterioles and capillary network in the brain of rats with different forms of hypertension. Microvasc Res ; 30 : 1 — 9. Paiardi S , Rodella LF , De Ciuceis C , Porteri E , Boari GE , Rezzani R , Rizzardi N , Platto C , Tiberio GA , Giulini SM , Rizzoni D , Agabiti-Rosei E.

Immunohistochemical evaluation of microvascular rarefaction in hypertensive humans and in spontaneously hypertensive rats. Clin Hemorheol Microcirc ; 42 : — Yamakawa H , Jezova M , Ando H , Saavedra JM.

Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition.

J Cereb Blood Flow Metab ; 23 : — Ouk M , Wu CY , Rabin JS , Jackson A , Edwards JD , Ramirez J , Masellis M , Swartz RH , Herrmann N , Lanctôt KL , Black SE , Swardfager W. The use of angiotensin-converting enzyme inhibitors vs. Alzheimers Res Ther ; 13 : Exp Neurol ; : — Kasparová S , Brezová V , Valko M , Horecký J , Mlynárik V , Liptaj T , Vancová O , Ulicná O , Dobrota D.

Study of the oxidative stress in a rat model of chronic brain hypoperfusion. Neurochem Int ; 46 : — Won JS , Kim J , Annamalai B , Shunmugavel A , Singh I , Singh AK.

Protective role of S-nitrosoglutathione GSNO against cognitive impairment in rat model of chronic cerebral hypoperfusion. J Alzheimers Dis ; 34 : — Catalpol promotes oligodendrocyte survival and oligodendrocyte progenitor differentiation via the Akt signaling pathway in rats with chronic cerebral hypoperfusion.

Brain Res ; : 27 — Farkas E , Donka G , de Vos RA , Mihály A , Bari F , Luiten PG. Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain.

Acta Neuropathol ; : 57 — Cruz Hernández JC , Bracko O , Kersbergen CJ , Muse V , Haft-Javaherian M , Berg M , Park L , Vinarcsik LK , Ivasyk I , Rivera DA , Kang Y , Cortes-Canteli M , Peyrounette M , Doyeux V , Smith A , Zhou J , Otte G , Beverly JD , Davenport E , Davit Y , Lin CP , Strickland S , Iadecola C , Lorthois S , Nishimura N , Schaffer CB.

Nat Neurosci ; 22 : — Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol ; 36 : — Davidson SM. Endothelial mitochondria and heart disease. Cardiovasc Res ; 88 : 58 — Marnett LJ , Rowlinson SW , Goodwin DC , Kalgutkar AS , Lanzo CA.

Arachidonic acid oxygenation by COX-1 and COX Mechanisms of catalysis and inhibition. J Biol Chem ; : — Bolduc V , Thorin-Trescases N , Thorin E. Endothelium-dependent control of cerebrovascular functions through age: exercise for healthy cerebrovascular aging.

Longden TA , Dabertrand F , Koide M , Gonzales AL , Tykocki NR , Brayden JE , Hill-Eubanks D , Nelson MT. Nat Neurosci ; 20 : — Frösen J , Cebral J , Robertson AM , Aoki T. Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms.

Neurosurg Focus ; 47 : E Ostrow LW , Suchyna TM , Sachs F. Stretch induced endothelin-1 secretion by adult rat astrocytes involves calcium influx via stretch-activated ion channels SACs. Biochem Biophys Res Commun ; : 81 — Saavedra JM , Nishimura Y. Angiotensin and cerebral blood flow.

Cell Mol Neurobiol ; 19 : — Phillips SJ , Whisnant JP. Hypertension and the brain. The National High Blood Pressure Education Program. Arch Intern Med ; : — Toth P , Tucsek Z , Sosnowska D , Gautam T , Mitschelen M , Tarantini S , Deak F , Koller A , Sonntag WE , Csiszar A , Ungvari Z.

Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab ; 33 : — Armstead WM , Hekierski H , Pastor P , Yarovoi S , Higazi AA , Cines DB.

Release of IL-6 after stroke contributes to impaired cerebral autoregulation and hippocampal neuronal necrosis through NMDA receptor activation and upregulation of ET-1 and JNK. Transl Stroke Res ; 10 : — Oyarce MP , Iturriaga R. Proinflammatory cytokines in the nucleus of the solitary tract of hypertensive rats exposed to chronic intermittent hypoxia.

Adv Exp Med Biol ; : 69 — Crippa IA , Subirà C , Vincent JL , Fernandez RF , Hernandez SC , Cavicchi FZ , Creteur J , Taccone FS. Accordingly, inflammation and immune system activation cause derangement in kidneys, arteries, brain, and heart functions that consequently promote hypertension and end-organ damage [ 57 ].

In support of the above mentioned hypothesis, current studies indicated that known stimuli that raise blood pressure such as high-salt diet, Ang II, and DOCA-salt directly and indirectly activate immune system cells. Elevated blood pressure can stress tissue cells to the level that DAMPs released by tissues.

Moreover, hypertensive stimuli can directly activate immune cells and also cause formation of neoantigens in the tissues. As a result of released DAMPs, neoantigens, and direct immune cells activation by hypertension stimuli, activated immune cells are formed, target organs infiltrated by activated immune cells, and diverse inflammatory cytokines are released by the activated immune cells.

Eventually, the affected target organs, mainly the kidney, blood vessels, and sympathetic nervous system function are perturbed and this leads to further elevated blood pressure level and finally to hypertension. Immune cells such as monocytes, macrophages, and dendritic cells DCs release pro-hypertensive cytokines that promote the BP elevation via actions in the vasculature augmenting vascular dysfunction , kidney increasing sodium retention , and stimulating sympathetic nervous system outflow [ 58 ].

Many studies implicated that in the kidney, inflammatory cells and their products contribute to blood pressure elevation at least in part by increasing renal sodium transport [ 59 ]. Genetic deletion of IL-6 in mice results in blunted hypertension in response to angiotensin II infusion [ 60 ].

Taken together, these studies suggest that IL-6 enhances renal tubule sodium reabsorption and elevates BP at least in part through up regulation of renal tubule ENaC. IL-1 is a pro-inflammatory cytokine that plays a central role in both acute and chronic inflammation, acting as a primary inducer of the innate immune response.

Studies indicated that type 1 IL-1 receptor IL-1R1 stimulation by IL-1 potentiates blood pressure elevation by suppressing nitric oxide NO -dependent sodium excretion in the kidney.

Nitric oxide is a potent driver of sodium excretion in the kidney that acts via cyclic guanosine monophosphate cGMP and phosphodiesterase two to limit Na-K-2Cl cotransporter NKCC2 activity in the medullary thick ascending limb. Thus, by relieving NO inhibitory effect on NKCC2, IL-1 enhances reabsorption of electrolytes by medullary thick ascending limb and enhances retention of sodium and water by kidney [ 39 ].

Interferon gamma IFN-γ is a proinflammatory cytokine produced by innate and adaptive immune cells, and T cell production of IFN-γ is increased in Ang II-induced hypertension and mice deficient in IFN-γ have a blunted blood pressure response to Ang II infusion.

Experimental studies indicate that IFN-γ positively regulates sodium hydrogen exchanger 3 NHE3 in the proximal tubule, NKCC2 in medullary thick ascending limb, and NCC in the distal tubule. Whether IFN-γ directly modulates these sodium transporters or acts through downstream mediators is unknown [ 62 ].

Mice model experimental studies and cell culture model studies showed that interleukin 17A up regulates NHE3 in proximal segment , NCC and ENaC in distal segment of renal tubules. Moreover, studies implicated that interleukin 17A regulates renal sodium transporters through a serum and glucocorticoid regulated kinase 1 SGK1 dependent pathway [ 63 ].

Serum and glucocorticoid regulated kinase1 is an important mediator of salt and water retention in the kidney through inhibition of neural precursor cell expressed developmentally down-regulated Nedd mediated ubiquitination and degradation of NHE3, NCC, and ENaC in the renal tubule, thereby enhancing the expression of these transporters on the cell surface [ 64 ].

Besides its effect on electrolyte and water homeostasis regulation function of kidney, sustained inflammation results in renal fibrosis, oxidative stress, glomerular injury, and chronic kidney disease [ 59 ]. Blood vessels are other organs that are affected by activated immune system and chronic low grade inflammation associated with hypertension.

Elevated blood pressure has an impact on the vasculature as a consequence of both the mechanical effects of blood pressure and shear stress [ 65 ]. Inflammation can impair blood vessels in two ways. Inflammation can cause functional arterial stiffening by impairing the functional relaxation capability of arteries.

The other mechanism is structural remodeling of arteries due to hypertension-associated inflammation [ 66 ]. Likewise, many experimental studies confirmed involvement of immune cells and inflammatory cytokines in vascular dysfunction associated with experimental hypertension.

An experimental study done on mice showed that Ang II infusion in mice increased immune cell content T cells, macrophages, and dendritic cells in perivascular adipose tissue and adventitia [ 67 ].

Endothelial cell culture study showed that inflammatory marker, C-reactive protein CRP , caused a marked down regulation of endothelial nitric oxide synthase eNOS mRNA and protein expression [ 68 ]. Similarly, TNF-α mediated inhibition of eNOS expression was observed in endothelial cell culture [ 69 ].

Acute treatment of endothelial cells with IL caused a significant increase in phosphorylation of the inhibitory eNOS residue threonine eNOS Thr [ 70 ]. All these studies indicate that inflammation decreases bioavailability of endothelial NO and thus impairs vascular smooth muscle relaxation and subsequent vasodilatations.

Moreover, involvement of immune cells and inflammatory cytokines in hypertensive vascular remodeling is implicated by many studies.

These studies implicated that immune cells and inflammatory cytokines play roles in vascular fibrosis, remodeling of small and large vessels, and vascular rarefaction in hypertension. Nonetheless, this remains to be further investigated.

Other important organ both in development of hypertension and as an end-organ target of hypertension is the brain. Regulation of short-term blood pressure level by sympathetic nervous system SNS is well established.

SNS stimulation is associated with constriction of blood vessels, increased cardiac output, and augmented sodium and fluid retention by the kidneys [ 72 ]. Moreover, SNS serves as an integrative interface between the brain and the immune system.

Mounting evidence implicate that many forms of essential hypertension are initiated and maintained by an elevated sympathetic tone [ 73 ]. The elevated sympathetic activity can be initiated by several factors including humoral factors such as angiotensin II and by environmental factors such as stress and high salt intake.

Observations such as increased splenic sympathetic nerve discharge SND and consequent increase in splenic cytokine gene expression IL-1β, IL-6, IL-2, and IL due to central Ang II administration the effect which was abrogated by splenic sympathetic denervation , and others led to the hypothesis that central stimuli such as angiotensin II cause modest elevations of blood pressure, which leads to activation of immune system.

Subsequently, the activated immune system leads to severe hypertension [ 76 ]. This hypothesis proposed a mechanism that occurs in a two-phase feed forward fashion.

The initial phase brings a modest elevation in blood pressure i. In the second phase, the activated immune system generates cytokines and other inflammatory mediators which work in concert with the direct effects of hypertensive stimuli such as angiotensin II, catecholamines, and salt to cause vascular and renal dysfunction, promote vasoconstriction, vascular remodeling, a shift in the pressure-natriuresis curve and sodium retention, and ultimately causes sustained hypertension [ 74 ].

Hypertension is a widely prevalent public health problem of world adult population. It is a major risk factor of cardiovascular diseases, chronic kidney disease, and dementia. This indicates lack of efficacy of existing hypertension treatment strategies and existence of additional drivers of hypertension that must be identified and may be targeted.

One of the proposed pathophysiologic mechanisms that contribute for elevated BP and target organ damage among hypertensive patients is activation of the immune system and chronic low grade systemic inflammation.

In kidneys, inflammatory cells and their products contribute to blood pressure elevation by increasing renal sodium retention and by causing renal fibrosis, oxidative stress, and glomerular injury. IL-1, IL-6, IFN-γ, and IL are among pro-inflammatory cytokines that enhance sodium retention by renal tubules.

Activated immune cells and pro-inflammatory cytokines may contribute to functional arterial stiffening and structural remodeling of arteries that consequently cause elevated blood pressure in hypertension.

C-reactive protein, TNF-α, and IL may hamper synthesis of or inhibit nitric oxide NO synthase. Inflammatory cells that infiltrate blood vessels such as macrophages and lymphocytes and their pro-inflammatory products may also contribute for vascular remodeling.

Perturbed immune system and chronic low grade systemic inflammation also enhance SNS activity which in turn contributes to elevated blood pressure by its effect on blood vessels tone vasoconstriction , on the kidneys sodium and water retention, RAAS activation and on immune system activation of immune system and enhanced production pro-inflammatory cytokines.

Thus, unraveling the detail pathophysiological mechanisms by which activated immune system and inflammation contribute to hypertension paves a way to identify target, and to design and develop therapeutic intervention for hypertension.

Even though currently there is no anti-inflammatory drug to treat hypertension, anti-inflammatory agents that target specific inflammatory pathway without compromising general immune system of an individual are possible future hypertension treatment drugs.

Author does not have any conflict of interest whatsoever with regard to content or opinions expressed above. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Naofumi Shiomi. Open access peer-reviewed chapter Immune System and Inflammation in Hypertension Written By Mohammed Ibrahim Sadik.

DOWNLOAD FOR FREE Share Cite Cite this chapter There are two ways to cite this chapter:. Choose citation style Select style Vancouver APA Harvard IEEE MLA Chicago Copy to clipboard Get citation. Choose citation style Select format Bibtex RIS Download citation. IntechOpen Lifestyle-Related Diseases and Metabolic Syndrome Edited by Naofumi Shiomi.

From the Edited Volume Lifestyle-Related Diseases and Metabolic Syndrome Edited by Naofumi Shiomi Book Details Order Print.

Chapter metrics overview Chapter Downloads View Full Metrics. Impact of this chapter. Abstract Hypertension is a widely prevalent and a major modifiable risk factor for cardiovascular diseases.

Keywords hypertension immune system inflammation. References 1. Williams B, Mancia G, Spiering W, Agabiti RE, Azizi M, Burnier M, et al.

European Heart Journal. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al. Fuchs FD, Whelton PK. High blood pressure and cardiovascular disease.

Stanaway JD, Afshin A, Gakidou E, Lim SS, Abate D, Abate KH, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for countries and territories, A systematic analysis for the Global Burden of Disease Study.

The Lancet. Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global disparities of hypertension prevalence and control: A systematic analysis of population-based studies from 90 countries. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J.

Global burden of hypertension: Analysis of worldwide data. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison HC, et al. Journal of the American College of Cardiology. Geldsetzer P, Manne GJ, Marcus ME, Ebert C, Zhumadilov Z, Wesseh CS, et al.

The state of hypertension care in 44 low-income and middle-income countries: A cross-sectional study of nationally representative individual-level data from 1.

Wenzel UO, Ehmke H, Bode M. Immune mechanisms in arterial hypertension. Recent advances. Cell and Tissue Research. Dinh QN, Drummond GR, Sobey CG, Chrissobolis S. Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. BioMed Research International.

Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Meizlish ML, Franklin RA, Zhou X, Medzhitov R. Tissue homeostasis and inflammation. Annual Review of Immunology. Chovatiya R, Medzhitov R.

Stress, inflammation, and defense of homeostasis. Molecular Cell. Medzhitov R. Origin and physiological roles of inflammation. Parkin J, Cohen B. An overview of the immune system.

Marshall JS, Warrington R, Watson W, Kim HL. An introduction to immunology and immunopathology. Turvey SE, Broide DH. Innate immunity. The Journal of Allergy and Clinical Immunology.

Yatim KM, Lakkis FG. A brief journey through the immune system. Clinical Journal of the American Society of Nephrology. Paul WE. Bridging innate and adaptive immunity. Bonilla FA, Oettgen HC. Adaptive immunity. Rönnbäck C, Hansson E. The importance and control of low-grade inflammation due to damage of cellular barrier systems that may lead to systemic inflammation.

Frontiers in Neurology. Furman D, Campisi J, Verdin E, Carrera BP, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span.

Nature Medicine. Tkacova R. Systemic inflammation in chronic obstructive pulmonary disease: may adipose tissue play a role? Review of the literature and future perspectives. Mediators of Inflammation. Chen Y, Liu S, Leng SX.

Chronic low-grade inflammatory phenotype CLIP and senescent immune dysregulation. Clinical Therapeutics. Trott DW, Harrison DG. The immune system in hypertension.

Advances in Physiology Education. Blake GJ, Rifai N, Buring JE, Ridker PM. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Bautista LE, Atwood JE, O'Malley PG, Taylor AJ.

Association between C-reactive protein and hypertension in healthy middle-aged men and women. Coronary Artery Disease. Xu T, Ju Z, Tong W, Hu W, Liu Y, Zhao L, et al. Relationship of C-reactive protein with hypertension and interactions between increased C-reactive protein and other risk factors on hypertension in Mongolian people.

Chinese Circulation Journal. Dauphinot V, Roche F, Kossovsky MP, Schott AM, Pichot V, Gaspoz JM, et al. C-reactive protein implications in new-onset hypertension in a healthy population initially aged 65 years: the Proof study. Journal of Hypertension. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM.

C-reactive protein and the risk of developing hypertension. The Journal of the American Medical Association. Bautista LE, Vera LM, Arenas IA, Gamarra G.

Independent association between inflammatory markers C-reactive protein, interleukin-6, and TNF-α and essential hypertension.

Journal of Human Hypertension. Chae CU, Lee RT, Rifai N, Ridker PM. Blood pressure and inflammation in apparently healthy men. Dalekos GN, Elisaf M, Bairaktari E, Tsolas O, Siamopoulos KC.

Increased serum levels of interleukin-1β in the systemic circulation of patients with essential hypertension: Additional risk factor for atherogenesis in hypertensive patients? Journal of Laboratory and Clinical Medicine. Simvastatin reduces interleukin-1β secretion by peripheral blood mononuclear cells in patients with essential hypertension.

Clinica Chimica Acta. Zhang W, Wang W, Yu H, Zhang Y, Dai Y, Ning C, et al. Interleukin 6 underlies angiotensin II—induced hypertension and chronic renal damage. Crosswhite P, Sun Z.

Ribonucleic acid interference knockdown of interleukin 6 attenuates cold-induced hypertension. Sriramula S, Haque M, Majid DS, Francis J.

Involvement of tumor necrosis factor-α in angiotensin II—mediated effects on salt appetite, hypertension, and cardiac hypertrophy.

Zhang J, Rudemiller NP, Patel MB, Karlovich NS, Wu M, McDonough AA, et al. Interleukin-1 augments salt retention in angiotensin II-induced hypertension via nitric oxide-dependent regulation of the NKCC2 sodium co-transporter.

Cell Metabolism. Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, et al. Interleukin 17 promotes angiotensin II—induced hypertension and vascular dysfunction. Gellert M. V D J recombination: RAG proteins, repair factors, and regulation.

Annual Review of Biochemistry. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II—induced hypertension and vascular dysfunction. Journal of Experimental Medicine. Trott DW, Thabet SR, Kirabo A, Saleh MA, Itani H, Norlander AE, et al.

Begg SK, Radley JM, Pollard JW, Chisholm OT, Stanley ER, Bertoncello I.

com HealthEconomics. Com BioPharmCatalyst Subscribe. Inflammation and Vascular Damage in Hypertension. DATE: Wednesday, September 28, DURATION: 60 MIN. Watch webinar.

Access Resources. Inflammation and Vascular Damage in Hypertension Sydney Otomancek T Watch Dr. Ana Briones present her research on the effects and potential therapeutic targets of excessive inflammation and vascular damage in hypertension.

Key Topics Include:. To understand the contribution of excessive inflammation to vascular damage in hypertension To understand the effects of proresolvin lipid mediators at the vascular level To consider resolution of inflammation as a new therapeutic approach for the management of vascular damage associated to hypertension.

Click to watch the webinar recording. To view the presentation full screen simply click the square icon located in the bottom-right corner of the video-viewer. ExpertAnswers: Ana Briones on Targeting Inflammation and Vascular Damage in Hypertension. Inflammation and Vascular Damage in Hypertension from InsideScientific.

Ana Briones, PhD, PharmD. Professor Pharmacology Universidad Autónoma de Madrid. Ana Briones is Associate Professor at the Pharmacology Department in the Universidad Autónoma de Madrid Spain.

Her lab is focused on the role of inflammation and resolution of inflammation in the cardiovascular damage associated to hypertension, obesity, and aneurysms. Production Partner. Kent Scientific Corporation. For over 30 years, Kent Scientific serviced scientists as a provider of integrated solutions for pre-clinical research and drug discovery advancement.

VIEW PROFILE. Additional Content From Kent Scientific Corporation. Control of Muscle Glucose Uptake in vivo: Thinking Outside the Myocyte In this webinar, David Wasserman, PhD provides a more complete understanding of muscle glucose uptake through consideration of the integration of physiological systems that control this process.

Simple Tips to Significantly Improve Rodent Surgical Outcomes Dr. Ann Rheum Dis. Article Google Scholar. Gabriel S. Heart disease in rheumatoid arthritis: changing the paradigm of systemic inflammatory disorders. J Rheumatol. PubMed Google Scholar. Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC.

Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Navarro-Millan I, Yang S, DuVall SL, Chen L, Baddley J, Cannon GW, Delzell ES, Zhang J, Safford MM, Patkar NM, et al.

Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration.

Charles-Schoeman C, Fleischmann R, Davignon J, Schwartz H, Turner SM, Beysen C, Milad M, Hellerstein MK, Luo Z, Kaplan IV, et al. Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib.

Arthritis Rheumatol. Liao KP, Playford MP, Frits M, Coblyn JS, Iannaccone C, Weinblatt ME, Shadick NS, Mehta NN. The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis.

J Am Heart Assoc. Robertson J, Porter D, Sattar N, Packard CJ, Caslake M, McInnes I, McCarey D. Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis.

del Rincon I, Polak JF, O'Leary DH, Battafarano DF, Erikson JM, Restrepo JF, Molina E, Escalante A. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis.

Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, et al.

A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. Peters SA, Huxley RR, Woodward M. Comparison of the sex-specific associations between systolic blood pressure and the risk of cardiovascular disease: a systematic review and meta-analysis of cohort studies, including 1.

Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.

Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol. McQuillan GM, McLean JE, Chiappa M, Lukacs SL.

National Health and Nutrition Examination Survey biospecimen program: NHANES III — and NHANES — National Center for Health Statistics. Vital Health Stat. Nalichowski R, Keogh D, Chueh HC, Murphy SN. Calculating the benefits of a research patient data repository.

AMIA Annu Symp Proc. Carroll RJ, Thompson WK, Eyler AE, Mandelin AM, Cai T, Zink RM, Pacheco JA, Boomershine CS, Lasko TA, Xu H, et al. Portability of an algorithm to identify rheumatoid arthritis in electronic health records. J Am Med Inform Assoc. Liao KP, Cai T, Gainer V, Goryachev S, Zeng-treitler Q, Raychaudhuri S, Szolovits P, Churchill S, Murphy S, Kohane I, et al.

Electronic medical records for discovery research in rheumatoid arthritis. Arthritis Care Res. Ong KL, Allison MA, Cheung BM, Wu BJ, Barter PJ, Rye KA. Trends in C-reactive protein levels in US adults from to Yoon SS, Fryar CD, Carroll MD.

Hypertension prevalence and control among adults: United States, — NCHS data brief, no Hyattsville, MD: National Center for Health Statistics; Whicher JT, Ritchie RF, Johnson AM, Baudner S, Bienvenu J, Blirup-Jensen S, Carlstrom A, Dati F, Ward AM, Svendsen PJ.

New international reference preparation for proteins in human serum RPPHS. Clin Chem. CAS PubMed Google Scholar. Hastie TJ, Tibshirani RJ. Generalized additive models. New York: Chapman and Hall; Myers GL, Rifai N, Tracy RP, Roberts WL, Alexander RW, Biasucci LM, Catravas JD, Cole TG, Cooper GR, Khan BV, et al.

Kushner I, Rzewnicki D, Samols D. What does minor elevation of C-reactive protein signify? Am J Med. Rozman B, Praprotnik S, Logar D, Tomsic M, Hojnik M, Kos-Golja M, Accetto R, Dolenc P. Leflunomide and hypertension. Manavathongchai S, Bian A, Rho YH, Oeser A, Solus JF, Gebretsadik T, Shintani A, Stein CM.

Inflammation and hypertension in rheumatoid arthritis. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third international consensus definitions for sepsis and septic shock Sepsis Schouten M, Wiersinga WJ, Levi M, van der Poll T.

Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. Hardy ST, Loehr LR, Butler KR, Chakladar S, Chang PP, Folsom AR, Heiss G, MacLehose RF, Matsushita K, Avery CL. Reducing the blood pressure-related burden of cardiovascular disease: impact of achievable improvements in blood pressure prevention and control.

Myasoedova E, Crowson CS, Kremers HM, Roger VL, Fitz-Gibbon PD, Therneau TM, Gabriel SE. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease.

Navarro-Millan I, Charles-Schoeman C, Yang S, Bathon JM, Bridges SL Jr, Chen L, Cofield SS, Dell'Italia LJ, Moreland LW, O'Dell JR, et al. Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial.

Arthritis Rheum. Dessein PH, Joffe BI. Insulin resistance and impaired beta cell function in rheumatoid arthritis. Chung CP, Oeser A, Solus JF, Gebretsadik T, Shintani A, Avalos I, Sokka T, Raggi P, Pincus T, Stein CM. Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms.

Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, et al. Crowson CS, Matteson EL, Roger VL, Therneau TM, Gabriel SE. Usefulness of risk scores to estimate the risk of cardiovascular disease in patients with rheumatoid arthritis.

Am J Cardiol. Kawai VK, Chung CP, Solus JF, Oeser A, Raggi P, Stein CM. Arts EE, Popa C, Den Broeder AA, Semb AG, Toms T, Kitas GD, van Riel PL, Fransen J. Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis.

Duong M, Salvo F, Pariente A, Abouelfath A, Lassalle R, Droz C, Blin P, Moore N. prescription-strength nonsteroidal anti-inflammatory drugs in France. Br J Clin Pharmacol.

Adams RJ, Appleton SL, Gill TK, Taylor AW, Wilson DH, Hill CL. Cause for concern in the use of non-steroidal anti-inflammatory medications in the community—a population-based study.

BMC Fam Pract. Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep.

Klocke R, Cockcroft JR, Taylor GJ, Hall IR, Blake DR. Arterial stiffness and central blood pressure, as determined by pulse wave analysis, in rheumatoid arthritis. Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, Bechir M, Spieker LE, Neidhart M, Michel BA, et al.

Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Karbach S, Croxford AL, Oelze M, Schuler R, Minwegen D, Wegner J, Koukes L, Yogev N, Nikolaev A, Reissig S, et al. Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.

Arterioscler Thromb Vasc Biol. Beigel R, Dvir D, Arbel Y, Shechter A, Feinberg MS, Shechter M. Pulse pressure is a predictor of vascular endothelial function in middle-aged subjects with no apparent heart disease.

Vasc Med. Download references. This study was supported by the grants R01 HL, P30 AR, R01 EB, U54 LM, U01 HG, and U54 HG, and from the National Institutes of Health, PCORI The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Outpatient population data that support the findings of this study are available from the Partners RPDR, but restrictions apply to the availability of these data. Data are, however, available from the authors upon reasonable request and with permission from the RPDR. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Seoyoung C. Kim, Kathleen Vanni, Jie Huang, Daniel H. Research Computing, Partners HealthCare, Charlestown, MA, USA. Laboratory of Computer Science, Massachusetts General Hospital, Boston, MA, USA.

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. You can also search for this author in PubMed Google Scholar. ZY, SK, RD, DH, and KL contributed to study conception and design; ZY, KV, JH, SM, and KL contributed to data acquisition and analysis; ZY, SK, RD, JH, DH, and KL contributed to interpretation of data; ZY and KPL had primary responsibility for final content; all authors contributed to critical revision and approved the final manuscript.

Correspondence to Katherine P. He serves in an unpaid capacity on a Pfizer-sponsored trial on an unrelated topic. He receives royalties from UpToDate on unrelated topics.

No other authors report any disclosures. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Figure S1. RA, rheumatoid arthritis; NHANES, National Health and Nutrition Examination Survey.

PDF kb. Figure S2. Figure S3. Figure S4. Table S1. DOCX 17 kb. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Yu, Z. et al. Association between inflammation and systolic blood pressure in RA compared to patients without RA.

Arthritis Res Ther 20 , Download citation. Received : 02 December Accepted : 18 April Published : 01 June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Research article Open access Published: 01 June Association between inflammation and systolic blood pressure in RA compared to patients without RA Zhi Yu 1 , 2 , Seoyoung C.

Kim 3 , 4 , Kathleen Vanni 3 , Jie Huang 3 , Rishi Desai 4 , Shawn N. Murphy 5 , 6 , 7 , Daniel H. This article has been updated. Abstract Background The relationship between inflammation and blood pressure BP has been studied mainly in the general population.

Methods We studied subjects from a tertiary care outpatient population with C-reactive protein CRP and BP measured on the same date in —; RA outpatients were identified using a validated algorithm.

Results We studied 24, subjects from the outpatient population, of whom had RA, and were from NHANES. Conclusions Across a broad range of CRP observed in RA and non-RA outpatients, we found an inverse U-shaped relationship between CRP and SBP, highlighting a relationship not previously observed when studying the general population.

Background Inflammation is associated with elevated blood pressure BP in the general population [ 1 , 2 ]. Methods Study populations General population cohort The National Health and Nutrition Examination Survey NHANES served as the general population control for this study [ 17 ]. CRP and BP measurements In the NHANES cohort, CRP was measured using a high-sensitivity assay with latex-enhanced nephelometry [ 21 ].

Statistical analysis For the primary analysis, we focused on the association between CRP and SBP because it is the main target of BP intervention studies of CVD risk [ 13 ]. Results A total of 24, subjects were included in the outpatient population, of whom had RA RA outpatient population and 22, did not non-RA outpatient population.

Table 1 Clinical characteristic of subjects in the RA outpatient population, non-RA outpatient population and the general population NHANES Full size table. Full size image. Discussion In summary, our study corroborates previous reports of a positive linear association between CRP and SBP.

Conclusions In conclusion, our study suggests that CRP, used as a marker of inflammation, has a biphasic relationship with SBP when examining the relationship across the range of CRP levels observed in RA and in the outpatient setting. References Bautista LE, Vera LM, Arenas IA, Gamarra G.

Article CAS Google Scholar Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. Article CAS Google Scholar Iannaccone CK, Lee YC, Cui J, Frits ML, Glass RJ, Plenge RM, Solomon DH, Weinblatt ME, Shadick NA. Article CAS Google Scholar Ridker PM, Buring JE, Rifai N, Cook NR.

Article CAS Google Scholar Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Article Google Scholar Gabriel S.

PubMed Google Scholar Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC. Article Google Scholar Navarro-Millan I, Yang S, DuVall SL, Chen L, Baddley J, Cannon GW, Delzell ES, Zhang J, Safford MM, Patkar NM, et al.

Article Google Scholar Charles-Schoeman C, Fleischmann R, Davignon J, Schwartz H, Turner SM, Beysen C, Milad M, Hellerstein MK, Luo Z, Kaplan IV, et al. Article CAS Google Scholar Liao KP, Playford MP, Frits M, Coblyn JS, Iannaccone C, Weinblatt ME, Shadick NS, Mehta NN. Article CAS Google Scholar del Rincon I, Polak JF, O'Leary DH, Battafarano DF, Erikson JM, Restrepo JF, Molina E, Escalante A.

Article CAS Google Scholar Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, et al. Article CAS Google Scholar Peters SA, Huxley RR, Woodward M. Article Google Scholar Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K.

Article Google Scholar Kuller LH, Tracy RP, Shaten J, Meilahn EN. Article CAS Google Scholar McQuillan GM, McLean JE, Chiappa M, Lukacs SL. Article Google Scholar Liao KP, Cai T, Gainer V, Goryachev S, Zeng-treitler Q, Raychaudhuri S, Szolovits P, Churchill S, Murphy S, Kohane I, et al.

Article Google Scholar Ong KL, Allison MA, Cheung BM, Wu BJ, Barter PJ, Rye KA. Article Google Scholar Yoon SS, Fryar CD, Carroll MD. CAS PubMed Google Scholar Hastie TJ, Tibshirani RJ. Article CAS Google Scholar Kushner I, Rzewnicki D, Samols D.

Article Google Scholar Rozman B, Praprotnik S, Logar D, Tomsic M, Hojnik M, Kos-Golja M, Accetto R, Dolenc P. Article CAS Google Scholar Manavathongchai S, Bian A, Rho YH, Oeser A, Solus JF, Gebretsadik T, Shintani A, Stein CM.

Article CAS Google Scholar Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. Article CAS Google Scholar Schouten M, Wiersinga WJ, Levi M, van der Poll T.

In an early study, Herrera et al. Notably, BP increased following MMF cessation in this study. The authors also demonstrated a reduction in urinary TNF-α was during MMF therapy. Ninety percent of these subjects had hypertension at baseline. Bubble plot illustrating immunomodulatory agents plotted by baseline SBP x -axis and average change in SBP y -axis , both in mmHg, with bubble area representing cohort size.

CNI, calcineurin inhibitor; CTLA4-Ig, cytotoxic T-lymphocyte-associated protein 4 immunoglobulin; HCQ, hydroxychloroquine; IL, interleukin; MMF, mycophenolate mofetil; mTOR: mammalian target of rapamycin; MTX: methotrexate; SBP, systolic blood pressure; TNF, tumour necrosis factor.

MTX is a chemotherapy agent and disease-modifying anti-rheumatic drug DMARD. Five studies involving between 20 and participants were identified, reporting average baseline SBP between and Only one of these employed ABPM. Average SBP lowering ranged from 1.

Hydroxychloroquine is an antimalarial agent that is used as a DMARD, and experimentally in IgA nephropathy. The largest of these involved patients with RA and showed that hydroxychloroquine lowered BP by 1.

Leflunomide is a pyrimidine synthesis inhibitor used in active RA and psoriatic arthritis. Calcineurin inhibitors CNIs block the earliest steps of T cell activation, but also have substantial off-target effects, including stimulation of endothelin production, increases in sympathetic outflow, renal vasoconstriction, salt retention, and hypertension Figure 4.

In four of these, the baseline BP was in the hypertensive range. Renal and immune system effects of calcineurin inhibitors influencing blood pressure. COX2, cyclooxygenase-2; GFR, glomerulofiltration rate; IL-2, interleukin-2; NFAT, nuclear factor of activated T cells; NO, nitric oxide; TMA, thrombotic microangiopathy; RAAS, renin—angiotensin—aldosterone system; ROS, reactive oxygen species; SNS, sympathetic nervous system; TGF-β, transforming growth factor beta.

Created in BioRender. Mammalian target of rapamycin mTOR inhibitors such as sirolimus and everolimus regulate cellular metabolism, growth, and proliferation, offering alternative immunosuppression following transplantation. This was dominated by reduction in nocturnal SBP in both the everolimus and cyclosporine arms.

Abatacept is composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 CTLA This agent targets T cell co-stimulation and is commonly used in transplant and rheumatologic diseases.

In five studies of RA patients reporting BP outcomes with abatacept, specific values were not available for two and none of the others reported a statistically significant effect on BP. All of these were in transplant recipients and were compared to patients receiving CNIs.

Two of these studies involved cross over from CNI to Belatacept and showed a SBP reduction of 5. One RCT reported no difference in mean SBP.

The apparent BP benefit with belatacept but not abatacept likely reflects population differences transplant vs. RA, respectively , potential physiological changes post-transplantation, and the cross-over effect from CNI, which as noted above, has off-target effects that can raise BP.

Rituximab is a monoclonal antibody against CD20, resulting in B cell apoptosis and depletion. It is used in lymphoid and blood malignancies and diverse autoimmune diseases. Trials reporting BP that are not confounded by polypharmacy were sparse.

In summary, trials in rheumatic, autoimmune, and transplant patients indicate a possible BP-lowering effect of selected anti-inflammatory therapies targeting diverse pathways previously identified by pre-clinical studies.

The evidence appears to be most consistent in relation to anti-TNF-α agents, while other therapies such as hydroxychloroquine, MMF, and mTORs all suggest BP-lowering effect Figures 3 and 5.

Data are however conflicting, and hypertension was rarely a pre-specified outcome measure. Trials often involved normotensive populations in which BP lowering is difficult to observe.

A combined analysis of studies discussed in this paper shows that cohorts with higher average baseline SBP appear to achieve greater BP-lowering effect Figure 3 , an association also reported for anti-hypertensive drugs.

Immunomodulatory drugs and the level of animal and clinical evidence available regarding blood pressure and organ system outcomes. Summarized according to the aggregated weight of the available evidence.

BP, blood pressure; CD, cluster of differentiation; CNI, calcineurin inhibitor; CTLA4-Ig, cytotoxic T-lymphocyte-associated protein 4 immunoglobulin; HCQ, hydroxychloroquine; IL, interleukin; MMF, mycophenolate mofetil; mTOR: mammalian target of rapamycin; MTX: methotrexate; TNF, tumour necrosis factor.

Includes chronic kidney disease, end-stage kidney disease, fibrosis, and inflammation. Several non - pharmacological treatment approaches have shown beneficial effects in reducing inflammation and therefore improving patient outcomes in the context of hypertension.

Animal studies suggest that periodontal Porphyromonas gingivalis infection increases IFN-γ and TNF-α production through modulation of Th1 responses, leading to BP elevation, endothelial dysfunction, and vascular inflammation.

As in the case of pharmacological interventions, BP reductions were not observed in normotensive individuals. For dietary interventions, most research has focused on CVD risk reduction, though BP lowering has also been demonstrated in both normotensive and hypertensive cohorts, , at least in part immune-mediated via effects of diet on the microbiome.

Dietary salt is another dominant driver of hypertension, primarily through activation of renin—angiotensin—aldosterone system ; at higher concentration, salt also favours pro-inflammatory monocyte and T cell phenotypes with increased tissue infiltration and microvascular dysfunction. The central nervous system regulates vascular and kidney function through sympathetic innervation but is also a potent modulator of immune responses.

Animal and human studies demonstrate the role of neuroimmune axis in the pathogenesis of hypertension, , with murine renal denervation RDN inducing a reduction in BP, — and reduction in renal inflammation, T cell activation, and pro-inflammatory cytokine production. One trial demonstrated reductions in TNF-α and IL-1β, and up-regulation of IL one day after RDN; however, this did not persist to day 3, and was not corroborated elsewhere.

An alternative approach to sympathetic denervation is augmentation of parasympathetic activity through vagus nerve stimulation VNS.

This approach has proven effective in hypertensive rodent models. Hypertension-mediated organ damage HMOD correlates with BP values in hypertension , ; however, genetics, lifestyle, and co-morbid conditions may also contribute to end-organ damage independently of BP levels.

Similarly, the target organ benefit of immunomodulation might be partially independent of BP effects. The strength of evidence regarding the effects of immunomodulatory therapy on HMOD in experimental and clinical settings is summarized in Figure 5.

This study reported a reduction in cardiovascular risk in response to numerous immunomodulatory drugs, including biologic agents HR: 0.

Nurmohamed et al. reviewed 90 studies reporting cardiovascular risk outcomes in rheumatological conditions treated with abatacept, TNF-α inhibitors, rituximab, secukinumab, tocilizumab, and tofacitinib. They report a neutral effect on BP, on surrogate markers of cardiovascular risk, and on MACE, though authors emphasise the variation in quantity and quality of evidence.

Colchicine is hypothesized to inhibit microtubular polymerization, assembly of the NLRP3 inflammasome, and IL-1β and IL production. In acute coronary syndrome, colchicine abrogates local increases in IL-1β, IL, and IL-6 levels, and its addition to aspirin and statin reduces high-sensitivity C-reactive protein.

Similarly, LoDoCo2 randomized chronic coronary disease patients to low-dose colchicine, with composite end-point events in 6. Overall, we would conclude that there is evidence of improvement in MACE for TNF-α inhibitors, MTX, tocilizumab, secukinumab, leflunomide and colchicine, though heterogeneity of study designs and outcomes limits the strength of this statement, and we have not explored the relationship between reduction in inflammation and MACE suggested by CANTOS and TNF-α inhibitor responders in the registry data above.

HMOD outcomes beyond MACE are surmised in Figure 5 for common immunomodulatory drugs. While experimental, genetic, and clinical evidence supports the role of inflammation and immune system involvement in hypertension and associated vascular, renal, and cardiac pathology, immunomodulatory approaches are not currently considered therapeutic options in BP lowering and cardiovascular disease reduction.

Indeed, clinical evidence reviewed in this paper shown a highly heterogeneous effect of immune targeting on BP and cardiovascular events across a wide range of patients mainly with various underlying immune-mediated diseases.

Going forward, there are several important considerations. As is the case with traditional anti-hypertensive medications, the BP-lowering effects of anti-inflammatory agents appear to be limited to those with uncontrolled hypertension. This is not surprising as numerous compensatory mechanisms make lowering beyond normal BP difficult.

It is also important to consider that the effects may be limited to patients with active pro-hypertensive inflammatory mechanisms.

The lesson from CIRT, TNF-α inhibitor responders vs. non-responders, CANTOS, and the body of the evidence presented is that there must be active inflammation. Secondly, we must target the optimal checkpoint in the inflammation—hypertension relationship to optimize benefit without adverse effect, and so far, this has remained elusive at a population level.

Finally, it is important to consider that virtually all of the preclinical studies investigating the anti-hypertensive effect of immune interventions on hypertension have involved treatment of animals at the onset on hypertension, often concomitantly with the onset of the disease.

In contrast, these agents are usually given to humans with long-standing hypertension. It is possible, and even likely that once hypertension has been established, there are chronic changes in renal and vascular function and structure that render such treatment less effective.

In this regard, treatment of younger individuals with early onset hypertension might yield different results than those observed in the studies summarized here.

Supplementary material is available at Cardiovascular Research online. Data derived from sources in the public domain. Reference details are provided in full. Statistical assistance was provided by Dr John McClure, University of Glasgow. Software used in the generating of this manuscript includes BioRender.

com figures , Minitab Statistical Software, and Meta-essentials meta-analysis. Tomasz Guzik and Pasquale Maffia have positions within CVR; the manuscript was handled by a consulting editor.

Libby P. The changing landscape of atherosclerosis. Nature ; : — Google Scholar. Liberale L , Montecucco F , Tardif JC , Libby P , Camici GG. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease.

Eur Heart J ; 41 : — Nus M , Mallat Z , Sage A. Beating T-lymphocyte driven atherosclerosis with B- and T-lymphocyte attenuator.

Cardiovasc Res ; : — van Kuijk K , Kuppe C , Betsholtz C , Vanlandewijck M , Kramann R , Sluimer JC. Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing.

Douna H , Amersfoort J , Schaftenaar FH , Kröner MJ , Kiss MG , Slütter B , Depuydt MAC , Bernabé Kleijn MNA , Wezel A , Smeets HJ , Yagita H , Binder CJ , Bot I , van Puijvelde GHM , Kuiper J , Foks AC. B- and T-lymphocyte attenuator stimulation protects against atherosclerosis by regulating follicular B cells.

Visseren FLJ , Mach F , Smulders YM , Carballo D , Koskinas KC , Bäck M , Benetos A , Biffi A , Boavida J-M , Capodanno D , Cosyns B , Crawford C , Davos CH , Desormais I , Di Angelantonio E , Franco OH , Halvorsen S , Hobbs FDR , Hollander M , Jankowska EA , Michal M , Sacco S , Sattar N , Tokgozoglu L , Tonstad S , Tsioufis KP , van Dis I , van Gelder IC , Wanner C , Williams B.

Eur Heart J ; 42 : — Steffens S , van LS , Sluijter JPG , Tocchetti CG , Thum T , Madonna R. Stimulating pro-reparative immune responses to prevent adverse cardiac remodelling: consensus document from the joint meeting of the ESC Working Groups of cellular biology of the heart and myocardial function.

Elnabawi YA , Dey AK , Goyal A , Groenendyk JW , Chung JH , Belur AD , Rodante J , Harrington CL , Teague HL , Baumer Y , Keel A , Playford MP , Sandfort V , Chen MY , Lockshin B , Gelfand JM , Bluemke DA , Mehta NN. Coronary artery plaque characteristics and treatment with biologic therapy in severe psoriasis: results from a prospective observational study.

Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med ; : — Ridker PM , Everett BM , Thuren T , MacFadyen JG , Chang WH , Ballantyne C , Fonseca F , Nicolau J , Koenig W , Anker SD , Kastelein JJP , Cornel JH , Pais P , Pella D , Genest J , Cifkova R , Lorenzatti A , Forster T , Kobalava Z , Vida-Simiti L , Flather M , Shimokawa H , Ogawa H , Dellborg M , Rossi PRF , Troquay RPT , Libby P , Glynn RJ , Krum H , Varigos J.

Antiinflammatory therapy with canakinumab for atherosclerotic disease. Nidorf SM , Fiolet ATL , Mosterd A , Eikelboom JW , Schut A , Opstal TSJ , The SHK , Xu X-F , Ireland MA , Lenderink T , Latchem D , Hoogslag P , Jerzewski A , Nierop P , Whelan A , Hendriks R , Swart H , Schaap J , Kuijper AFM , van Hessen MWJ , Saklani P , Tan I , Thompson AG , Morton A , Judkins C , Bax WA , Dirksen M , Alings M , Hankey GJ , Budgeon CA , Tijssen JGP , Cornel JH , Thompson PL ; LoDoCo2 Trial Investigators.

Colchicine in patients with chronic coronary disease. Weber BN , Blankstein R. Something old, something new: a paradigm for considering immune therapies for cardiovascular disease. Cardiovasc Res ; : e51 — e GBD Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for countries and territories, — a systematic analysis for the Global Burden of Disease Study Lancet ; : — Markó L , Park J-K , Henke N , Rong S , Balogh A , Klamer S , Bartolomaeus H , Wilck N , Ruland J , Forslund SK , Luft FC , Dechend R , Müller DN.

Grabie N , Lichtman AH , Padera R. T cell checkpoint regulators in the heart. Peet C , Ivetic A , Bromage DI , Shah AM. Cardiac monocytes and macrophages after myocardial infarction. Drummond GR , Vinh A , Guzik TJ , Sobey CG.

Immune mechanisms of hypertension. Nat Rev Immunol ; 19 : — Okuda T , Grollman A. Passive transfer of autoimmune induced hypertension in the rat by lymph node cells. Tex Rep Biol Med ; 25 : — Svendsen U. The role of thymus for the development and prognosis of hypertension and hypertensive vascular disease in mice following renal infarction.

Acta Pathol Microbiol Scand A ; 84 : — Svendsen UG. Influence of neonatal thymectomy on blood pressure and hypertensive vascular diseases in rats with renal hypertension. Acta Pathol Microbiol Scand A ; 83 : — Thymus dependency of periarteritis nodosa in DOCA and salt treated mice. Acta Pathol Microbiol Scand A ; 82 : 30 — Olsen F.

Transfer of arterial hypertension by splenic cells from DOCA-salt hypertensive and renal hypertensive rats to normotensive recipients.

Acta Pathol Microbiol Scand C ; 88 : 1 — 6. Evidence for an immunological factor in the hypertensive vascular disease. Acta Pathol Microbiol Scand A ; 79 : 22 — Vinh A , Chen W , Blinder Y , Weiss D , Taylor WR , Goronzy JJ , Weyand CM , Harrison DG , Guzik TJ.

Circulation ; : — Guzik TJ , Hoch NE , Brown KA , McCann LA , Rahman A , Dikalov S , Goronzy J , Weyand C , Harrison DG. Role of the T cell in the genesis of angiotensin II—induced hypertension and vascular dysfunction. J Exp Med ; : — Pollow DP , Uhrlaub J , Romero-Aleshire M , Sandberg K , Nikolich-Zugich J , Brooks HL , Hay M.

Sex differences in T-lymphocyte tissue infiltration and development of angiotensin II hypertension. Hypertension ; 64 : — Seniuk A , Thiele JL , Stubbe A , Oser P , Rosendahl A , Bode M , Meyer-Schwesinger C , Wenzel UO , Ehmke H.

Rag1 Knockout mice generated at the Jackson Laboratory in show a robust wild-type hypertensive phenotype in response to Ang II angiotensin II. Hypertension ; 75 : — Ji H , Pai AV , West CA , Wu X , Speth RC , Sandberg K.

Hypertension ; 69 : — Mattson DL , Lund H , Guo C , Rudemiller N , Geurts AM , Jacob H. Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. Am J Physiol Regul Integr Comp Physiol ; : R — R Crowley SD , Song Y-S , Lin EE , Griffiths R , Kim H-S , Ruiz P.

Lymphocyte responses exacerbate angiotensin II-dependent hypertension. Am J Physiol Regul Integr Comp Physiol ; : — Wu J , Thabet SR , Kirabo A , Trott DW , Saleh MA , Xiao L , Madhur MS , Chen W , Harrison DG.

Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res ; : — Trott DW , Thabet SR , Kirabo A , Saleh MA , Itani H , Norlander AE , Wu J , Goldstein A , Arendshorst WJ , Madhur MS , Chen W , Li C-I , Shyr Y , Harrison DG.

Kvakan H , Kleinewietfeld M , Qadri F , Park J-K , Fischer R , Schwarz I , Rahn H-P , Plehm R , Wellner M , Elitok S , Gratze P , Dechend R , Luft FC , Muller DN. Regulatory T cells ameliorate angiotensin II-induced cardiac damage. Barhoumi T , Kasal DA , Li MW , Shbat L , Laurant P , Neves MF , Paradis P , Schiffrin EL.

T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. Hypertension ; 57 : — Caillon A , Mian MOR , Fraulob-Aquino JC , Huo K-G , Barhoumi T , Ouerd S , Sinnaeve PR , Paradis P , Schiffrin EL.

γδ T cells mediate angiotensin II-induced hypertension and vascular injury. Wenzel P , Knorr M , Kossmann S , Stratmann J , Hausding M , Schuhmacher S , Karbach SH , Schwenk M , Yogev N , Schulz E , Oelze M , Grabbe S , Jonuleit H , Becker C , Daiber A , Waisman A , Münzel T.

Lysozyme M-positive monocytes mediate angiotensin ii-induced arterial hypertension and vascular dysfunction. Moore JP , Vinh A , Tuck KL , Sakkal S , Krishnan SM , Chan CT , Lieu M , Samuel CS , Diep H , Kemp-Harper BK , Tare M , Ricardo SD , Guzik TJ , Sobey CG , Drummond GR.

M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss and elevated blood pressure.

Am J Physiol Heart Circ Physiol ; : H — H De Ciuceis C , Amiri F , Brassard P , Endemann DH , Touyz RM , Schiffrin EL. Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury.

Arterioscler Thromb Vasc Biol ; 25 : — Macrophage depletion lowered blood pressure and attenuated hypertensive renal injury and fibrosis. Front Physiol ; 9 : e Hevia D , Araos P , Prado C , Luppichini Rojas FE , Alzamora M , Cifuentes-Araneda R , Gonzalez F , Amador AA , Pacheco CA , Michea R. Hypertension ; 71 : — Chan CT , Sobey CG , Lieu M , Ferens D , Kett MM , Diep H , Kim HA , Krishnan SM , Lewis CV , Salimova E , Tipping P , Vinh A , Samuel CS , Peter K , Guzik TJ , Kyaw TS , Toh BH , Bobik A , Drummond GR.

Obligatory role for B cells in the development of angiotensin II-dependent hypertension. Hypertension ; 66 : — Chen Y , Dale BL , Alexander MR , Xiao L , Ao M , Pandey AK , Smart CD , Davis GK , Madhur MS. Class switching and high-affinity immunoglobulin G production by B cells is dispensable for the development of hypertension in mice.

Kossmann S , Schwenk M , Hausding M , Karbach SH , Schmidgen MI , Brandt M , Knorr M , Hu H , Kröller-Schön S , Schönfelder T , Grabbe S , Oelze M , Daiber A , Münzel T , Becker C , Wenzel P.

Angiotensin ii-induced vascular dysfunction depends on interferon-γ- driven immune cell recruitment and mutual activation of monocytes and NK-cells.

Arterioscler Thromb Vasc Biol ; 33 : — Rodríguez-Iturbe B , Ferrebuz A , Vanegas V , Quiroz Y , Mezzano S , Vaziri ND. Early and sustained inhibition of nuclear factor-kappaB prevents hypertension in spontaneously hypertensive rats.

J Pharmacol Exp Ther ; : e51 — e Brands MW , Banes-Berceli AKL , Inscho EW , Al-Azawi H , Allen AJ , Labazi H. Hypertension ; 56 : — NLRP3 inflammasome activation is involved in Ang II-induced kidney damage via mitochondrial dysfunction.

Oncotarget ; 7 : — Renal tumor necrosis factor α contributes to hypertension in Dahl salt-sensitive rats. Sci Rep ; 6 : McShane L , Tabas I , Lemke G , Kurowska-Stolarska M , Maffia P.

TAM receptors in cardiovascular disease. Nosalski R , Mikolajczyk T , Siedlinski M , Saju B , Koziol J , Maffia P , Guzik TJ. Pharmacol Res ; : MacRitchie N , Grassia G , Noonan J , Cole JE , Hughes CE , Schroeder J , Benson RA , Cochain C , Zernecke A , Guzik TJ , Garside P , Monaco C , Maffia P.

Kirabo A , Fontana V , de Faria APC , Loperena R , Galindo CL , Wu J , Bikineyeva AT , Dikalov S , Xiao L , Chen W , Saleh MA , Trott DW , Itani HA , Vinh A , Amarnath V , Amarnath K , Guzik TJ , Bernstein KE , Shen XZ , Shyr Y , Chen S-C , Mernaugh RL , Laffer CL , Elijovich F , Davies SS , Moreno H , Madhur MS , Roberts J , Harrison DG.

DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest ; : — Krishnan SM , Dowling JK , Ling YH , Diep H , Chan CT , Ferens D , Kett MM , Pinar A , Samuel CS , Vinh A , Arumugam TV , Hewitson TD , Kemp-Harper BK , Robertson AAB , Cooper MA , Latz E , Mansell A , Sobey CG , Drummond GR.

Br J Pharmacol ; : — Carnevale D , Perrotta M , Pallante F , Fardella V , Iacobucci R , Fardella S , Carnevale L , Carnevale R , De LM , Cifelli G , Lembo G.

A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication. Nat Commun ; 7 : Carnevale D , Pallante F , Fardella V , Fardella S , Iacobucci R , Federici M , Cifelli G , De Lucia M , Lembo G.

The angiogenic factor PIGF mediates a neuroimmune interaction in the spleen to allow the onset of hypertension. Immunity ; 41 : — Rodriguez-Iturbe B , Lanaspa MA , Johnson RJ.

The role of autoimmune reactivity induced by heat shock protein 70 in the pathogenesis of essential hypertension. Idris-Khodja N , Mian MOR , Paradis P , Schiffrin EL. Dual opposing roles of adaptive immunity in hypertension. Eur Heart J ; 35 : — Madhur MS , Kirabo A , Guzik TJ , Harrison DG.

From rags to riches: moving beyond Rag1 in studies of hypertension. Xiao L , Harrison DG. Inflammation in hypertension. Can J Cardiol ; 36 : — Nosalski R , Siedlinski M , Denby L , McGinnigle E , Nowak M , Cat AND , Medina-Ruiz L , Cantini M , Skiba D , Wilk G , Osmenda G , Rodor J , Salmeron-Sanchez M , Graham G , Maffia P , Graham D , Baker AH , Guzik TJ.

T-cell-derived miRNA mediates perivascular fibrosis in hypertension. Hoyer FF , Nahrendorf M. Interferon-γ regulates cardiac myeloid cells in myocardial infarction. Abdellatif M , Zirlik A. Immunometabolism: a key target to improve microcirculation in ageing.

Cardiovasc Res ; : e48 — e Matrougui K , Abd Elmageed Z , Zakaria AE , Kassan M , Choi S , Nair D , Gonzalez-Villalobos RA , Chentoufi AA , Kadowitz P , Belmadani S , Partyka M.

Natural regulatory T cells control coronary arteriolar endothelial dysfunction in hypertensive mice. Am J Pathol ; : — Madhur MS , Lob HE , McCann LA , Iwakura Y , Blinder Y , Guzik TJ , Harrison DG.

Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension ; 55 : — Kamat N. V , Thabet SR , Xiao L , Saleh MA , Kirabo A , Madhur MS , Delpire E , Harrison DG , McDonough AA. Hypertension ; 65 : — Zhang J , Patel MB , Griffiths R , Mao A , Song Y , Karlovich NS , Sparks MA , Jin H , Wu M , Lin EE , Crowley SD.

Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension. Yvan-Charvet L , Bonacina F , Guinamard RR , Norata GD. Immunometabolic function of cholesterol in cardiovascular disease and beyond.

Filho AG , Kinote A , Pereira DJ , Rennó A , Dos Santos RC , Ferreira-Melo SE , Velloso LA , Bordin S , Anhê GF , Junior HM. Eur J Pharmacol ; : — Elmarakby AA , Quigley JE , Pollock DM , Imig JD. Tumor necrosis factor alpha blockade increases renal Cyp2c23 expression and slows the progression of renal damage in salt-sensitive hypertension.

Hypertension ; 47 : — Muller DN , Shagdarsuren E , Park J-K , Dechend R , Mervaala E , Hampich F , Fiebeler A , Ju X , Finckenberg P , Theuer J , Viedt C , Kreuzer J , Heidecke H , Haller H , Zenke M , Luft FC. Immunosuppressive treatment protects against angiotensin II-induced renal damage. Tran LT , MacLeod KM , McNeill JH.

Chronic etanercept treatment prevents the development of hypertension in fructose-fed rats. Mol Cell Biochem ; : — Venegas-Pont M , Manigrasso MB , Grifoni SC , LaMarca BB , Maric C , Racusen LC , Glover PH , Jones AV , Drummond HA , Ryan MJ.

Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus. Therrien FJ , Agharazii M , Lebel M , Larivière R. Neutralization of tumor necrosis factor-alpha reduces renal fibrosis and hypertension in rats with renal failure.

Am J Nephrol ; 36 : — Krishnan SM , Ling YH , Huuskes BM , Ferens DM , Saini N , Chan CT , Diep H , Kett MM , Samuel CS , Kemp-Harper BK , Robertson AAB , Cooper MA , Peter K , Latz E , Mansell AS , Sobey CG , Drummond GR , Vinh A.

Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension.

Cardiovasc Res ; 61 : — Cau SBA , Guimaraes DA , Rizzi E , Ceron CS , Gerlach RF , Tanus-Santos JE. The nuclear factor kappaB inhibitor pyrrolidine dithiocarbamate prevents cardiac remodelling and matrix metalloproteinase-2 up-regulation in renovascular hypertension. Basic Clin Pharmacol Toxicol ; : — Zhang J , Rudemiller NP , Patel MB , Karlovich NS , Wu M , McDonough AA , Griffiths R , Sparks MA , Jeffs AD , Crowley SD.

Interleukin-1 receptor activation potentiates salt reabsorption in angiotensin II-induced hypertension via the NKCC2 Co-transporter in the nephron. Cell Metab ; 23 : — Ling YH , Krishnan SM , Chan CT , Diep H , Ferens D , Chin-Dusting J , Kemp-Harper BK , Samuel CS , Hewitson TD , Latz E , Mansell A , Sobey CG , Drummond GR.

Pharmacol Res ; : 77 — Hashmat S , Rudemiller N , Lund H , Abais-Battad JM , Van Why S , Mattson DL. Interleukin-6 inhibition attenuates hypertension and associated renal damage in Dahl salt-sensitive rats. Am J Physiol Renal Physiol ; : F — F Mathis KW , Taylor EB , Ryan MJ.

Anti-CD3 antibody therapy attenuates the progression of hypertension in female mice with systemic lupus erythematosus. Pharmacol Res ; : — J Immunol ; : — Majeed B , Tawinwung S , Eberson LS , Secomb TW , Larmonier N , Larson DF. Int J Hypertens ; : Increasing regulatory T cells with interleukin-2 and interleukin-2 antibody complexes attenuates lung inflammation and heart failure progression.

Hypertension ; 68 : — T-cell mineralocorticoid receptor controls blood pressure by regulating interferon-gamma. Markó L , Kvakan H , Park JK , Qadri F , Spallek B , Binger KJ , Bowman EP , Kleinewietfeld M , Fokuhl V , Dechend R , Müller DN.

Interferon-γ signaling inhibition ameliorates angiotensin ii-induced cardiac damage. Hypertension ; 60 : — Amador CA , Barrientos V , Peña J , Herrada AA , González M , Valdés S , Carrasco L , Alzamora R , Figueroa F , Kalergis AM , Michea L.

Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes. Hypertension ; 63 : — Chiasson VL , Pakanati AR , Hernandez M , Young KJ , Bounds KR , Mitchell BM.

Regulatory T-cell augmentation or interleukin inhibition prevents calcineurin inhibitor-induced hypertension in mice. Hypertension ; 70 : — Saleh MA , Norlander AE , Madhur MS. Inhibition of interleukin A but not interleukinF signaling lowers blood pressure and reduces end-organ inflammation in angiotensin II-induced hypertension.

JACC Basic Transl Sci ; 1 : — Cornelius DC , Hogg JP , Scott J , Wallace K , Herse F , Moseley J , Wallukat G , Dechend R , LaMarca B. Administration of interleukin soluble receptor C suppresses TH17 cells, oxidative stress, and hypertension in response to placental ischemia during pregnancy.

Hypertension ; 62 : — Murphy SR , Dahly-Vernon AJ , Dunn KMJ , Chen CCA , Ledbetter SR , Williams JM , Roman RJ. Renoprotective effects of anti-TGF-β antibody and antihypertensive therapies in Dahl S rats. Am J Physiol Regul Integr Comp Physiol ; : R57 — R Chan CT , Moore JP , Budzyn K , Guida E , Diep H , Vinh A , Jones ES , Widdop RE , Armitage JA , Sakkal S , Ricardo SD , Sobey CG , Drummond GR.

Mikolajczyk TP , Nosalski R , Szczepaniak P , Budzyn K , Osmenda G , Skiba D , Sagan A , Wu J , Vinh A , Marvar PJ , Guzik B , Podolec J , Drummond G , Lob HE , Harrison DG , Guzik TJ.

Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension. FASEB J ; 30 : — De Batista PR , Palacios R , Martín A , Hernanz R , Médici CT , Silva MASC , Rossi EM , Aguado A , Vassallo DV , Salaices M , Alonso MJ.

Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production. PLoS One ; 9 : e Hernanz R , Martínez-Revelles S , Palacios R , Martín A , Cachofeiro V , Aguado A , García-Redondo L , Barrús MT , De Batista PR , Briones AM , Salaices M , Alonso MJ.

Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension. Bomfim GF , Echem C , Martins CB , Costa TJ , Sartoretto SM , Dos Santos RA , Oliveira MA , Akamine EH , Fortes ZB , Tostes RC , Webb RC , Carvalho MHC.

Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats. Life Sci ; : 1 — 7. Nunes KP , Bomfim GF , Toque HA , Szasz T , Clinton Webb R. Toll-like receptor 4 TLR4 impairs nitric oxide contributing to Angiotensin II-induced cavernosal dysfunction.

Life Sci ; : — Echem C , Bomfim GF , Ceravolo GS , Oliveira MA , Santos-Eichler RA , Bechara LR , Veras MM , Saldiva PHN , Ferreira JC , Akamine EH , Fortes ZB , Dantas AP , de Carvalho MHC. Anti-toll like receptor 4 TLR4 therapy diminishes cardiac remodeling regardless of changes in blood pressure in spontaneously hypertensive rats SHR.

Int J Cardiol ; : — McCarthy CG , Wenceslau CF , Goulopoulou S , Baban B , Matsumoto T , Webb RC. Chloroquine suppresses the development of hypertension in spontaneously hypertensive rats. Am J Hypertens ; 30 : — Cornelius DC , Castillo J , Porter J , Amaral LM , Campbell N , Paige A , Thomas AJ , Harmon A , Cunningham MW , Wallace K , Herse F , Wallukat G , Dechend R , LaMarca B.

Kumar V , Wollner C , Kurth T , Bukowy JD , Cowley AW. Inhibition of mammalian target of rapamycin complex 1 attenuates salt-induced hypertension and kidney injury in Dahl salt-sensitive rats.

Rodríguez-Iturbe B , Quiroz Y , Nava M , Bonet L , Chávez M , Herrera-Acosta J , Johnson RJ , Pons HA. Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats.

Am Jf Physiol Renal Physiol ; : F — F Boesen EI , Williams DL , Pollock JS , Pollock DM. Immunosuppression with mycophenolate mofetil attenuates the development of hypertension and albuminuria in deoxycorticosterone acetate-salt hypertensive rats.

Clin Exp Pharmacology Physiol ; 37 : — Taylor EB , Ryan MJ. Immunosuppression with mycophenolate mofetil attenuates hypertension in an experimental model of autoimmune disease. J Am Heart Assoc ; 6 : 1 — Tinsley JH , Chiasson VL , South S , Mahajan A , Mitchell BM.

Immunosuppression improves blood pressure and endothelial function in a rat model of pregnancy-induced hypertension. Am J Hypertens ; 22 : — COVID and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.

Bienvenu LA , Noonan J , Wang X , Peter K. Higher mortality of COVID in males: sex differences in immune response and cardiovascular comorbidities. Cardiovas Res ; : — Bautista LE , Vera LM , Arenas IA , Gamarra G. Independent association between inflammatory markers C-reactive protein, interleukin-6, and TNF-α and essential hypertension.

Jf Hum Hypertens ; 19 : — Puszkarska A , Niklas A , Głuszek J , Lipski D , Niklas K. The concentration of tumor necrosis factor in the blood serum and in the urine and selected early organ damages in patients with primary systemic arterial hypertension.

Medicine Baltimore ; 98 : e Association between the JNC 7 classification of the stages of systolic hypertension and inflammatory cardiovascular risk factors.

Korean Circ J ; 37 : — Di Napoli M , Papa F. Association between blood pressure and C-reactive protein levels in acute ischemic stroke.

Hypertension ; 42 : — Ridker PM , MacFadyen JG , Everett BM , Libby P , Thuren T , Glynn RJ , Ridker PM , MacFadyen JG , Everett BM , Libby P , Thuren T , Glynn RJ , Kastelein J , Koenig W , Genest J , Lorenzatti A , Varigos J , Siostrzonek P , Sinnaeve P , Fonseca F , Nicolau J , Gotcheva N , Yong H , Urina-Triana M , Milicic D , Cifkova R , Vettus R , Anker SD , Manolis AJ , Wyss F , Forster T , Sigurdsson A , Pais P , Fucili A , Ogawa H , Shimokawa H , Veze I , Petrauskiene B , Salvador L , Cornel JH , Klemsdal TO , Medina F , Budaj A , Vida-Simiti L , Kobalava Z , Otasevic P , Pella D , Lainscak M , Seung K-B , Commerford P , Dellborg M , Donath M , Hwang J-J , Kultursay H , Flather M , Ballantyne C , Bilazarian S , Chang W , East C , Forgosh L , Harris B , Ligueros M.

Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Stuveling EM , Hillege HL , Bakker SJL , Gans ROB , De Jong PE , De Zeeuw D. C-reactive protein is associated with renal function abnormalities in a non-diabetic population.

Kidney Int ; 63 : — Sesso HD , Wang L , Buring JE , Ridker PM , Gaziano JM. Comparison of interleukin-6 and C-reactive protein for the risk of developing hypertension in women. Hypertension ; 49 : — Schnabel R , Larson MG , Dupuis J , Lunetta KL , Lipinska I , Meigs JB , Yin X , Rong J , Vita JA , Newton-Cheh C , Levy D , Keaney JF , Vasan RS , Mitchell GF , Benjamin EJ.

Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection. Hypertension ; 51 : — Swerdlow DI , Holmes MV , Kuchenbaecker KB , Engmann JEL , Shah T , Sofat R , Guo Y , Chung C , Peasey A , Pfister R , Mooijaart SP , Ireland HA , Leusink M , Langenberg C , Li K , Palmen J , Howard P , Cooper JA , Drenos F , Hardy J , Nalls MA , Li YR , Lowe G , Stewart M , Bielinski SJ , Peto J , Timpson NJ , Gallacher J , Dunlop M , Houlston R.

The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis. Association of interleukin 6 receptor variant with cardiovascular disease effects of interleukin 6 receptor blocking therapy: a phenome - Wide association study.

JAMA Cardiol ; 3 : — Dalekos GN , Elisaf M , Bairaktari E , Tsolas O , Siamopoulos KC. Increased serum levels of interleukin-1β in the systemic circulation of patients with essential hypertension: additional risk factor for atherogenesis in hypertensive patients?

J Lab Clin Med ; : — Rabkin SW. The role of interleukin 18 in the pathogenesis of hypertension-induced vascular disease. Nat Clin Pract Cardiovasc Med ; 6 : — Madej A , Okopień B , Kowalski J , Haberka M , Herman ZS. Plasma concentrations of adhesion molecules and chemokines in patients with essential hypertension.

Pharmacol Rep ; 57 : — Carranza-Leon DA , Oeser A , Wu Q , Stein CM , Ormseth MJ , Chung CP. Ambulatory blood pressure in patients with systemic lupus erythematosus: association with markers of immune activation.

Lupus ; 29 : — Siedlinski M , Jozefczuk E , Xu X , Teumer A , Evangelou E , Schnabel RB , Welsh P , Maffia P , Erdmann J , Tomaszewski M , Caulfield MJ , Sattar N , Holmes MV , Guzik TJ. Pharm Biol ; 55 : — Iyonaga T , Shinohara K , Mastuura T , Hirooka Y , Tsutsui H.

Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation. Hypertens Res ; 43 : 99 — Abiodun OA , Ola MS. Role of brain renin angiotensin system in neurodegeneration: an update. Saudi J Biol Sci ; 27 : — Johanson C , Stopa E , McMillan P , Roth D , Funk J , Krinke G.

Toxicol Pathol ; 39 : — Saavedra JM. Brain and pituitary angiotensin. Endocr Rev ; 13 : — Allen AM , Zhuo J , Mendelsohn FA. Localization and function of angiotensin AT1 receptors. Am J Hypertens ; 13 : 31S — 38S. Mol Med Rep ; 12 : — Biancardi VC , Stranahan AM , Krause EG , de Kloet AD , Stern JE.

Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus. Glass MJ , Huang J , Speth RC , Iadecola C , Pickel VM. Angiotensin II AT-1A receptor immunolabeling in rat medial nucleus tractus solitarius neurons: subcellular targeting and relationships with catecholamines.

Sumners C , Alleyne A , Rodríguez V , Pioquinto DJ , Ludin JA , Kar S , Winder Z , Ortiz Y , Liu M , Krause EG , de Kloet AD. Brain angiotensin type-1 and type-2 receptors: cellular locations under normal and hypertensive conditions.

Hypertens Res ; 43 : — Faraco G , Sugiyama Y , Lane D , Garcia-Bonilla L , Chang H , Santisteban MM , Racchumi G , Murphy M , Van Rooijen N , Anrather J , Iadecola C. Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension.

J Clin Invest ; : — Zhang M , Mao Y , Ramirez SH , Tuma RF , Chabrashvili T. Angiotensin II induced cerebral microvascular inflammation and increased blood—brain barrier permeability via oxidative stress.

Iulita MF , Vallerand D , Beauvillier M , Haupert N , A Ulysse C , Gagné A , Vernoux N , Duchemin S , Boily M , Tremblay MÈ , Girouard H. Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice. J Neuroinflammation ; 15 : Capone C , Faraco G , Park L , Cao X , Davisson RL , Iadecola C.

The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. Biancardi VC , Son SJ , Ahmadi S , Filosa JA , Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood—brain barrier.

Hypertension ; 63 : — Jiang E , Chapp AD , Fan Y , Larson RA , Hahka T , Huber MJ , Yan J , Chen Q-H , Shan Z. Expression of proinflammatory cytokines is upregulated in the hypothalamic paraventricular nucleus of Dahl salt-sensitive hypertensive rats.

Front Physiol ; 9 : Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension.

Circulation ; 53 : — Barhoumi T , Kasal DA , Li MW , Shbat L , Laurant P , Neves MF , Paradis P , Schiffrin EL. T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury.

Hypertension ; 57 : — Kassan M , Galan M , Partyka M , Trebak M , Matrougui K. Arterioscler Thromb Vasc Biol ; 31 : — Kinzenbaw DA , Chu Y , Peña Silva RA , Didion SP , Faraci FM. Interleukin protects against aging-induced endothelial dysfunction.

Physiol Rep ; 1 : e Faraco G , Brea D , Garcia-Bonilla L , Wang G , Racchumi G , Chang H , Buendia I , Santisteban MM , Segarra SG , Koizumi K , Sugiyama Y , Murphy M , Voss H , Anrather J , Iadecola C.

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat Neurosci ; 21 : — Fujita M , Ando K , Nagae A , Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension.

Hypertension ; 50 : — Rodrigues SF , Granger DN. Cerebral microvascular inflammation in DOCA salt-induced hypertension: role of angiotensin II and mitochondrial superoxide.

J Cereb Blood Flow Metab ; 32 2 : — Santisteban MM , Ahn SJ , Lane D , Faraco G , Garcia-Bonilla L , Racchumi G , Poon C , Schaeffer S , Segarra SG , Körbelin J , Anrather J , Iadecola C.

Endothelium-macrophage crosstalk mediates blood—brain barrier dysfunction in hypertension. Hypertension ; 76 : — Wakisaka Y , Miller JD , Chu Y , Baumbach GL , Wilson S , Faraci FM , Sigmund CD , Heistad DD.

Oxidative stress through activation of NAD P H oxidase in hypertensive mice with spontaneous intracranial hemorrhage. J Cereb Blood Flow Metab ; 28 : — Shen XZ , Li Y , Li L , Shah KH , Bernstein KE , Lyden P , Shi P.

Microglia participate in neurogenic regulation of hypertension. Hypertension Dallas, Tex: ; 66 2 : — Dinh QN , Young MJ , Evans MA , Drummond GR , Sobey CG , Chrissobolis S.

Aldosterone-induced oxidative stress and inflammation in the brain are mediated by the endothelial cell mineralocorticoid receptor. Brain Res ; : — Chrissobolis S , Drummond GR , Faraci FM , Sobey CG.

Chronic aldosterone administration causes Nox2-mediated increases in reactive oxygen species production and endothelial dysfunction in the cerebral circulation. J Hypertens ; 32 : — Merrill DC , Thompson MW , Carney CL , Granwehr BP , Schlager G , Robillard JE , Sigmund CD.

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. J Clin Invest ; 97 : — Davisson RL , Yang G , Beltz TG , Cassell MD , Johnson AK , Sigmund CD. The brain renin—angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes.

Circ Res ; 83 : — Merrill DC , Granwehr BP , Davis DR , Sigmund CD. Use of transgenic and gene-targeted mice to model the genetic basis of hypertensive disorders.

Proc Assoc Am Physicians ; : — Baumbach GL , Sigmund CD , Faraci FM. Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen. Hypertension ; 41 : 50 — Baumbach GL , Heistad DD.

Cerebral circulation in chronic arterial hypertension. Hypertension ; 12 : 89 — Laurent S , Boutouyrie P , Lacolley P. Structural and genetic bases of arterial stiffness.

Hypertension ; 45 : — Spät A , Hunyady L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev ; 84 : — Han F , Ozawa H , Matsuda KI , Lu H , De Kloet ER , Kawata M. Changes in the expression of corticotrophin-releasing hormone, mineralocorticoid receptor and glucocorticoid receptor mRNAs in the hypothalamic paraventricular nucleus induced by fornix transection and adrenalectomy.

J Neuroendocrinol ; 19 : — Rigsby CS , Burch AE , Ogbi S , Pollock DM , Dorrance AM. Intact female stroke-prone hypertensive rats lack responsiveness to mineralocorticoid receptor antagonists. Am J Physiol Regul Integr Comp Physiol ; : R — R Gomez-Sanchez EP. Intracerebroventricular infusion of aldosterone induces hypertension in rats.

Endocrinology ; : — Kageyama Y , Bravo EL. Hypertensive mechanisms associated with centrally administered aldosterone in dogs. Hypertension ; 11 : — Francis J , Beltz T , Johnson AK , Felder RB. Mineralocorticoids act centrally to regulate blood-borne tumor necrosis factor-alpha in normal rats.

Dahl LK , Heine M , Tassinari L. Role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt ingestion. Jiang E , Chapp AD , Fan Y , Larson RA , Hahka T , Huber MJ , Yan J , Chen QH , Shan Z. Ueno Y , Mohara O , Brosnihan KB , Ferrario CM.

Characteristics of hormonal and neurogenic mechanisms of deoxycorticosterone-induced hypertension. Hypertension ; 11 : I — I Tynan RJ , Naicker S , Hinwood M , Nalivaiko E , Buller KM , Pow DV , Day TA , Walker FR.

Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav Immun ; 24 : — Gutkind JS , Kurihara M , Saavedra JM.

Increased angiotensin II receptors in brain nuclei of DOCA-salt hypertensive rats. Am J Physiol ; : H — H Schenk J , McNeill JH. The pathogenesis of DOCA-salt hypertension. J Pharmacol Toxicol Methods ; 27 : — Matthews KA , Katholi CR , McCreath H , Whooley MA , Williams DR , Zhu S , Markovitz JH.

Blood pressure reactivity to psychological stress predicts hypertension in the CARDIA study. Circulation ; : 74 — Marvar PJ , Vinh A , Thabet S , Lob HE , Geem D , Ressler KJ , Harrison DG.

T lymphocytes and vascular inflammation contribute to stress-dependent hypertension. Biol Psychiatry ; 71 : — Chronic stress decreases cerebrovascular responses during rat hindlimb electrical stimulation. Front Neurosci ; 9 : Behav Brain Res ; : — Wilson RS , Arnold SE , Schneider JA , Li Y , Bennett DA.

Chronic distress, age-related neuropathology, and late-life dementia. Psychosom Med ; 69 : 47 — Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun ; 16 : — Yaffe K , Lindquist K , Penninx BW , Simonsick EM , Pahor M , Kritchevsky S , Launer L , Kuller L , Rubin S , Harris T.

Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology ; 61 : 76 — Braszko JJ , Wincewicz D , Jakubów P. Candesartan prevents impairment of recall caused by repeated stress in rats. Psychopharmacology Berl ; : — Don-Doncow N , Vanherle L , Zhang Y , Meissner A.

T-cell accumulation in the hypertensive brain: a role for sphingosinephosphate-mediated chemotaxis. Int J Mol Sci ; 20 3 : Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging ; 33 : e19 — Poulet R , Gentile MT , Vecchione C , Distaso M , Aretini A , Fratta L , Russo G , Echart C , Maffei A , De Simoni MG , Lembo G.

Acute hypertension induces oxidative stress in brain tissues. J Cereb Blood Flow Metab ; 26 : — Sadekova N , Iulita MF , Vallerand D , Muhire G , Bourmoum M , Claing A , Girouard H.

Arterial stiffness induced by carotid calcification leads to cerebral gliosis mediated by oxidative stress. J Hypertens ; 36 : — Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature.

Hypertension Dallas, Tex: ; 60 : — Mestas J , Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol ; : — Daneman R. The blood—brain barrier in health and disease. Ann Neurol ; 72 : — Maktabi MA , Heistad DD , Faraci FM. Effects of central and intravascular angiotensin I and II on the choroid plexus.

Am J Physiol ; : R — R Villaseñor R , Ozmen L , Messaddeq N , Grüninger F , Loetscher H , Keller A , Betsholtz C , Freskgård PO , Collin L. Trafficking of endogenous immunoglobulins by endothelial cells at the blood—brain barrier. Sci Rep ; 6 : Korn T , Kallies A. T cell responses in the central nervous system.

Nat Rev Immunol ; 17 : — Baruch K , Deczkowska A , Rosenzweig N , Tsitsou-Kampeli A , Sharif AM , Matcovitch-Natan O , Kertser A , David E , Amit I , Schwartz M. Nat Med ; 22 : — Chodobski A , Szmydynger-Chodobska J , Johanson CE.

Angiotensin II regulates choroid plexus blood flow by interacting with the sympathetic nervous system and nitric oxide. Meningeal lymphatic vessels regulate brain tumor drainage and immunity.

Cell Res ; 30 : — Mestre H , Mori Y , Nedergaard M. Trends Neurosci ; 43 : — Mestre H , Tithof J , Du T , Song W , Peng W , Sweeney AM , Olveda G , Thomas JH , Nedergaard M , Kelley DH. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension.

Nat Commun ; 9 : Hunt BJ , Jurd KM. Endothelial cell activation. A central pathophysiological process. BMJ Clinical Research ed ; : — Ludewig P , Winneberger J , Magnus T. The cerebral endothelial cell as a key regulator of inflammatory processes in sterile inflammation.

J Neuroimmunol ; : 38 — Zhou H , Andonegui G , Wong CH , Kubes P. Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation.

CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation. J Neuroinflamm ; 12 : Ludewig P , Sedlacik J , Gelderblom M , Bernreuther C , Korkusuz Y , Wagener C , Gerloff C , Fiehler J , Magnus T , Horst AK.

Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMPmediated blood—brain-barrier breakdown in a mouse model for ischemic stroke.

Reglero-Real N , Colom B , Bodkin JV , Nourshargh S. Endothelial cell junctional adhesion molecules: role and regulation of expression in inflammation. Arterioscler Thromb Vasc Biol ; 36 : — Pan W , Kastin AJ , Daniel J , Yu C , Baryshnikova LM , von Bartheld CS.

TNFalpha trafficking in cerebral vascular endothelial cells. J Neuroimmunol ; : 47 — Fujimoto K. Pericyte—endothelial gap junctions in developing rat cerebral capillaries: a fine structural study. Anat Rec ; : — Liu S , Agalliu D , Yu C , Fisher M.

The role of pericytes in blood—brain barrier function and stroke. Curr Pharm Des ; 18 : — What is a pericyte? J Cereb Blood Flow Metab ; 36 : — Hirunpattarasilp C , Attwell D , Freitas F.

The role of pericytes in brain disorders: from the periphery to the brain. Capillary pericytes regulate cerebral blood flow in health and disease. Nature ; : 55 — Sweeney MD , Ayyadurai S , Zlokovic BV.

Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci ; 19 : — Berthiaume AA , Hartmann DA , Majesky MW , Bhat NR , Shih AY. Pericyte structural remodeling in cerebrovascular health and homeostasis. Front Aging Neurosci ; 10 : Activated microglia induce the production of reactive oxygen species and promote apoptosis of co-cultured retinal microvascular pericytes.

Graefes Arch Clin Exp Ophthalmol ; : — Al Ahmad A , Gassmann M , Ogunshola OO. Maintaining blood—brain barrier integrity: pericytes perform better than astrocytes during prolonged oxygen deprivation. J Cell Physiol ; : — Abbott NJ , Rönnbäck L , Hansson E.

Astrocyte—endothelial interactions at the blood—brain barrier. Nat Rev Neurosci ; 7 1 : 41 — Igarashi Y , Utsumi H , Chiba H , Yamada-Sasamori Y , Tobioka H , Kamimura Y , Furuuchi K , Kokai Y , Nakagawa T , Mori M , Sawada N. Glial cell line-derived neurotrophic factor induces barrier function of endothelial cells forming the blood—brain barrier.

Biochem Biophys Res Commun ; : — Heinemann U , Kaufer D , Friedman A. Blood—brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy.

Glia ; 60 : — Prat A , Biernacki K , Wosik K , Antel JP. Glial cell influence on the human blood—brain barrier. Glia ; 36 : — Lee SW , Kim WJ , Choi YK , Song HS , Son MJ , Gelman IH , Kim YJ , Kim KW.

SSeCKS regulates angiogenesis and tight junction formation in blood—brain barrier. Nat Med ; 9 : — Michinaga S , Koyama Y. Dual roles of astrocyte-derived factors in regulation of blood—brain barrier function after brain damage.

Lécuyer M-A , Kebir H , Prat A. Glial influences on BBB functions and molecular players in immune cell trafficking. Biochimica et Biophysica Acta BBA - Molecular Basis of Disease ; 3 : — Cipollini V , Anrather J , Orzi F , Iadecola C. Th17 and cognitive impairment: Possible mechanisms of action.

Front Neuroanat ; 13 : Mantle JL , Lee KH. A differentiating neural stem cell-derived astrocytic population mitigates the inflammatory effects of TNF-α and IL-6 in an iPSC-based blood—brain barrier model. Neurobiol Dis ; : — De Silva TM , Faraci FM. In Caplan LR , Biller J , Leary MC , Lo EH, Thomas AJ , Yenari M , et al.

eds , Primer on Cerebrovascular Diseases, 2nd edn. Academic Press : San Diego , , pp — Sokolova IA , Manukhina EB , Blinkov SM , Koshelev VB , Pinelis VG , Rodionov IM. Rarefication of the arterioles and capillary network in the brain of rats with different forms of hypertension.

Microvasc Res ; 30 : 1 — 9. Paiardi S , Rodella LF , De Ciuceis C , Porteri E , Boari GE , Rezzani R , Rizzardi N , Platto C , Tiberio GA , Giulini SM , Rizzoni D , Agabiti-Rosei E.

Immunohistochemical evaluation of microvascular rarefaction in hypertensive humans and in spontaneously hypertensive rats. Clin Hemorheol Microcirc ; 42 : — Yamakawa H , Jezova M , Ando H , Saavedra JM.

Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab ; 23 : — Ouk M , Wu CY , Rabin JS , Jackson A , Edwards JD , Ramirez J , Masellis M , Swartz RH , Herrmann N , Lanctôt KL , Black SE , Swardfager W.

The use of angiotensin-converting enzyme inhibitors vs. Alzheimers Res Ther ; 13 : Exp Neurol ; : — Kasparová S , Brezová V , Valko M , Horecký J , Mlynárik V , Liptaj T , Vancová O , Ulicná O , Dobrota D.

Study of the oxidative stress in a rat model of chronic brain hypoperfusion. Neurochem Int ; 46 : — Won JS , Kim J , Annamalai B , Shunmugavel A , Singh I , Singh AK. Protective role of S-nitrosoglutathione GSNO against cognitive impairment in rat model of chronic cerebral hypoperfusion.

J Alzheimers Dis ; 34 : — Catalpol promotes oligodendrocyte survival and oligodendrocyte progenitor differentiation via the Akt signaling pathway in rats with chronic cerebral hypoperfusion. Brain Res ; : 27 — Farkas E , Donka G , de Vos RA , Mihály A , Bari F , Luiten PG.

Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain. Acta Neuropathol ; : 57 — Cruz Hernández JC , Bracko O , Kersbergen CJ , Muse V , Haft-Javaherian M , Berg M , Park L , Vinarcsik LK , Ivasyk I , Rivera DA , Kang Y , Cortes-Canteli M , Peyrounette M , Doyeux V , Smith A , Zhou J , Otte G , Beverly JD , Davenport E , Davit Y , Lin CP , Strickland S , Iadecola C , Lorthois S , Nishimura N , Schaffer CB.

Nat Neurosci ; 22 : — Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol ; 36 : — Davidson SM.

Endothelial mitochondria and heart disease. Cardiovasc Res ; 88 : 58 — Marnett LJ , Rowlinson SW , Goodwin DC , Kalgutkar AS , Lanzo CA. Arachidonic acid oxygenation by COX-1 and COX Mechanisms of catalysis and inhibition.

J Biol Chem ; : — Bolduc V , Thorin-Trescases N , Thorin E. Endothelium-dependent control of cerebrovascular functions through age: exercise for healthy cerebrovascular aging. Longden TA , Dabertrand F , Koide M , Gonzales AL , Tykocki NR , Brayden JE , Hill-Eubanks D , Nelson MT.

Nat Neurosci ; 20 : — Frösen J , Cebral J , Robertson AM , Aoki T. Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms.

Neurosurg Focus ; 47 : E Ostrow LW , Suchyna TM , Sachs F. Stretch induced endothelin-1 secretion by adult rat astrocytes involves calcium influx via stretch-activated ion channels SACs. Biochem Biophys Res Commun ; : 81 — Saavedra JM , Nishimura Y.

Angiotensin and cerebral blood flow. Cell Mol Neurobiol ; 19 : — Phillips SJ , Whisnant JP. Hypertension and the brain.

The National High Blood Pressure Education Program. Arch Intern Med ; : — Toth P , Tucsek Z , Sosnowska D , Gautam T , Mitschelen M , Tarantini S , Deak F , Koller A , Sonntag WE , Csiszar A , Ungvari Z. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension.

J Cereb Blood Flow Metab ; 33 : — Armstead WM , Hekierski H , Pastor P , Yarovoi S , Higazi AA , Cines DB. Release of IL-6 after stroke contributes to impaired cerebral autoregulation and hippocampal neuronal necrosis through NMDA receptor activation and upregulation of ET-1 and JNK.

Transl Stroke Res ; 10 : — Oyarce MP , Iturriaga R. Proinflammatory cytokines in the nucleus of the solitary tract of hypertensive rats exposed to chronic intermittent hypoxia. Adv Exp Med Biol ; : 69 — Crippa IA , Subirà C , Vincent JL , Fernandez RF , Hernandez SC , Cavicchi FZ , Creteur J , Taccone FS.

Impaired cerebral autoregulation is associated with brain dysfunction in patients with sepsis. Crit Care ; 22 : Berg RM , Plovsing RR , Evans KA , Christiansen CB , Bailey DM , Holstein-Rathlou NH , Møller K.

Lipopolysaccharide infusion enhances dynamic cerebral autoregulation without affecting cerebral oxygen vasoreactivity in healthy volunteers. Crit Care ; 17 : R Taccone FS , Su F , De Deyne C , Abdellhai A , Pierrakos C , He X , Donadello K , Dewitte O , Vincent J-L , De Backer D.

Sepsis is associated with altered cerebral microcirculation and tissue hypoxia in experimental peritonitis. Crit Care Med ; 42 2 : e — e Rosengarten B , Hecht M , Wolff S , Kaps M.

Autoregulative function in the brain in an endotoxic rat shock model. Inflamm Res ; 57 : — Venkat P , Chopp M , Chen J. New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain. Croat Med J ; 57 : — Kisler K , Nelson AR , Montagne A , Zlokovic BV.

Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci ; 18 : — Sofroniew MV , Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol ; : 7 — Boche D , Perry VH , Nicoll JA. Review: activation patterns of microglia and their identification in the human brain.

Neuropathol Appl Neurobiol ; 39 : 3 — Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci ; 32 12 : — McConnell HL , Kersch CN , Woltjer RL , Neuwelt EA. The translational significance of the neurovascular unit. Girouard H , Iadecola C.

Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol ; : — Stanimirovic DB , Friedman A.

Pathophysiology of the neurovascular unit: disease cause or consequence? J Cereb Blood Flow Metab ; 32 : — Heneka MT , Kummer MP , Latz E. Innate immune activation in neurodegenerative disease.

Nat Rev Immunol ; 14 : — Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci ; 16 : — Takata N , Nagai T , Ozawa K , Oe Y , Mikoshiba K , Hirase H. PLoS One ; 8 : e Nizar K , Uhlirova H , Tian P , Saisan PA , Cheng Q , Reznichenko L , Weldy KL , Steed TC , Sridhar VB , MacDonald CL , Cui J , Gratiy SL , Sakadzić S , Boas DA , Beka TI , Einevoll GT , Chen J , Masliah E , Dale AM , Silva GA , Devor A.

In vivo stimulus-induced vasodilation occurs without IP3 receptor activation and may precede astrocytic calcium increase.

J Neurosci ; 33 19 : — Institoris Á , Rosenegger DG , Gordon GR. J Cereb Blood Flow Metab ; 35 : — Filosa JA , Morrison HW , Iddings JA , Du W , Kim KJ. Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone.

Neuroscience ; : 96 — Mishra A , Reynolds JP , Chen Y , Gourine AV , Rusakov DA , Attwell D. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles.

Gordon GR , Choi HB , Rungta RL , Ellis-Davies GC , MacVicar BA. Brain metabolism dictates the polarity of astrocyte control over arterioles. Metea MR , Newman EA. Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling.

J Neurosci ; 26 : — Kim KJ , Iddings JA , Stern JE , Blanco VM , Croom D , Kirov SA , Filosa JA. J Neurosci ; 35 21 : — Girouard H , Bonev AD , Hannah RM , Meredith A , Aldrich RW , Nelson MT.

Proc Natl Acad Sci U S A ; 8 : McConnell HL , Li Z , Woltjer RL , Mishra A. Astrocyte dysfunction and neurovascular impairment in neurological disorders: correlation or causation?

Neurochem Int ; : 70 — Proc Natl Acad Sci U S A ; : — Hermann K , Phillips MI , Hilgenfeldt U , Raizada MK. Biosynthesis of angiotensinogen and angiotensins by brain cells in primary culture.

J Neurochem ; 51 : — Jiang MH , Höög A , Ma KC , Nie XJ , Olsson Y , Zhang WW. Endothelinlike immunoreactivity is expressed in human reactive astrocytes. Neuroreport ; 4 : — High glucose-induced expression of inflammatory cytokines and reactive oxygen species in cultured astrocytes.

Neuroscience ; : 58 — Gowrisankar YV , Clark MA. Angiotensin II induces interleukin-6 expression in astrocytes: role of reactive oxygen species and NF-κB. Mol Cell Endocrinol ; : — Iulita MF , Duchemin S , Vallerand D , Barhoumi T , Alvarez F , Istomine R , Laurent C , Youwakim J , Paradis P , Arbour N , Piccirillo CA , Schiffrin EL , Girouard H.

J Am Heart Assoc ; 8 : e Girouard H , Park L , Anrather J , Zhou P , Iadecola C. Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II. Arterioscler Thromb Vasc Biol ; 27 : — Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through Noxderived radicals.

Arterioscler Thromb Vasc Biol ; 26 : — Kazama K , Anrather J , Zhou P , Girouard H , Frys K , Milner TA , Iadecola C. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals.

Circ Res ; 95 : — Kandalam U , Palanisamy M , Clark MA. Angiotensin II induces cell growth and IL-6 mRNA expression through the JAK2-STAT3 pathway in rat cerebellar astrocytes.