Central and Peripheral Mechanisms of T lymphocyte Activation and Vascular Inflammation Produced by Angiotensin II-Induced Hypertension

• Type of Material: Article
• Authors: Paul Marvar, Emory University; Salim R. Thabet, Emory University; Tomasz J. Guzik, School of Medicine, Atlanta, GA, 303221; Heinrich E. Lob, Emory University; Louise A. McCann, Emory University; Connie Weyand, Emory University; Frank J Gordon, Emory University; David G Harrison, Emory University
• Language: English
• Date: 2010-07-23
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 American Heart Association, Inc
• Final Published Version (URL): http://dx.crossref.org/10.1161%2FCIRCRESAHA.110.217299
• Title of Journal or Parent Work: Circulation Research
• ISSN: 0009-7330
• Volume: 107
• Issue: 2
• Start Page: 263
• End Page: 270
• Grant/Funding Information: Supported by NIH Program Project Grant HL59006, P01 HL58000, P01 HL095070; NRSA F32 Foundation for Polish Science from funds of European Union (FNP/Welcome/2009/02) and European Molecular Biology Organization.; Dr. Guzik was supported by the EMBO Young Investigator Program and the Polish Ministry of Science and Technology.; his work was supported by NIH grants HL390006 and HL59248, NIH Program Project Grant HL58000, HL63919 and EY11916 and a Department of Veterans Affairs Merit Grant. Dr. Marvar was supported by an NIH F32 individual post doctoral fellowship grant.
• Keywords: Hypertension; T cells; vascular inflammation; central nervous system
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Rationale We have previously found that T lymphocytes are essential for development of angiotensin II-induced hypertension however the mechanisms responsible for T cell activation in hypertension remain undefined. Objective To study the roles of the central nervous system and pressure elevation in T cell activation and vascular inflammation caused by angiotensin II. Methods and Results To prevent the central actions of angiotensin II we created anteroventral third cerebral ventricle (AV3V) lesions in mice. The elevation in blood pressure in response to angiotensin II was virtually eliminated by AV3V lesions, as was activation of circulating T cells and the vascular infiltration of leukocytes. In contrast, AV3V lesioning did not prevent the hypertension and T cell activation caused by the peripheral acting agonist norepinephrine. To determine if T cell activation and vascular inflammation are due to central influences or are mediated by blood pressure elevation, we administered hydralazine (250 mg/L) in the drinking water. Hydralazine prevented the hypertension, and abrogated the increase in circulating activated T cells and vascular infiltration of leukocytes caused by angiotensin II. Conclusions We conclude that the central and pressor effects of angiotensin II are critical for T cell activation and development of vascular inflammation. These findings also support a feed forward mechanism in which modest degrees of blood pressure elevation lead to T cell activation, which in turn promotes inflammation and further raises blood pressure, leading to severe hypertension. Brief summary We have previously shown that T cells are important for the development of hypertension and others have shown that CNS lesions such as AV3V disruption prevent hypertension. We examined the relationship between central actions of angiotensin II, T cell activation and hypertension by determining how AV3V lesions affect T cell activation and hypertensive responses to angiotensin II and norepinephrine. Our data are compatible with a scenario in which modest degrees of pressure elevation, mediated either directly by norepinephrine or via central actions of angiotensin II, promote an inflammatory response that leads to severe hypertension. These studies provide new insight into how the central nervous system contributes to systemic inflammation in hypertension.