The Central Nervous System and T-Cells in Angiotensin II Induced Hypertension

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DESCRIPTION (provided by applicant): During the past 2 decades, it has become clear that reactive oxygen species (ROS) are important in the genesis of numerous vascular diseases, including atherosclerosis and hypertension. The production of ROS is increased in numerous conditions that cause vascular disease, including hypercholesterolemia, diabetes, hypertension, smoking and aging. It has also become evident that the major sources of ROS in vascular and non-vascular cells are the NADPH oxidases which are present in many relevant organs, including the vessel, the kidney and the brain. Preliminary studies suggest that the T cell is essential for hypertension caused by angiotensin II and may explain how activation of the NADPH oxidases in various organs, such as the brain leads to hypertension. The effects of angiotensin II on the central nervous system have long been known to contribute to sustained hypertension and recent work from others suggests that angiotension II causes hypertension via a ROS mediated mechanism, involving the NADPH oxidase in the circumventricular organs of the brain. The overall goal of this proposal is to investigate whether the CNS actions of angiotensin II contributes to T cell activation of NADPH oxidases and increased generation of ROS during angiotensin II induced hypertension. I propose that the effects of angiotensin II on the central nervous system can lead to T cell activation. Activated T cells then act on vessels and likely the kidney and via cytokine release stimulate local NADPH oxidases that promote hypertension. In this proposal, I will specifically focus on how angiotensin II may mediate this process via the CNS and I will address the following specific aims to test this hypothesis. Specific aim 1 will examine the role of the CNS in T-cell activation following angiotensin II induced hypertension. Specific aim 2 will determine whether the CNS and the T cell contribute to increased NADPH oxidase activity and reactive oxygen species (ROS) generation caused by angiotensin ll-mediated hypertension. Specific aim 3 will examine the role of the CNS and the T cell in contributing to the vascular dysfunction caused by angiotensin II induced hypertension. To examine these aims I will perform ablation of the anteroventral third ventricle (AV3V) region of the brain and also specifically delete the NADPH oxidase subunit p22phox in the circumventricular organs. The data generated from this proposal will enhance our knowledge of the mechanisms of hypertension as it relates to angiotensin II and will broaden our understanding of the relationships between inflammation, ROS and vascular disease.