The long-term objective of this project is to identify mechanisms by which chronic hypertension alters structure and function of cerebral blood vessels. During chronic hypertension, cerebral blood vessels undergo hypertrophy and """"""""remodeling"""""""" (defined as a reduction in external diameter), both of which have important hemodynamic implications. Hyperhomocysteinemia also may produce vascular hypertrophy, and may be a major risk factor for stroke. The proposed studies will utilize genetically-altered mice to examine three specific aims related to there observations.
The first aim i s to examine effects of the renin-angiotensin system on cerebral arterioles in genetic and nongenetic chronic hypertension. The investigators propose to use an in vivo method to measure cerebral arteriolar pressure (servonull) and diameter, histological methods to determine cross-sectional area of the arteriolar wall, and unilateral carotid clipping to attenuate increases in arteriolar pressure. Renin-angiotensinogen double transgenic (R plus/A plus) mice will be examined to test the hypothesis that increased activity of the renin-angiotensin system contributes to remodeling of cerebral arterioles in genetic hypertension. Spontaneously hypertensive (BPH-2) mice, a genetic model of hypertension that is not renin dependent, will be used to determine whether remodeling of cerebral arterioles may not occur in genetic hypertension with normal renin activity. To examine the hypothesis that cerebral arterioles may not occur in genetic hypertension with normal renin activity. To examine the hypothesis that cerebral arterioles do not undergo remodeling in nongenetic hypertension, the investigators will examine effects of chronic infusion of angiotensin II in wild-type mice.
The second aim i s to examine effects of nitric oxide (NO) and endothelia-1 on cerebral vascular structure. The hypothesis that NO plays a role in cerebral vascular growth during normotension will be examined in endothelial NO synthase knockout (eNOS00) mice. In a second study, eNOSo/0/R plus/A plus mice will be generated to determine whether NO may be a determinant of cerebral vascular hypertrophy during chronic hypertension. In a third study, eNOS0/0 mice will be treated with an endothelia receptor (ET-A and ET-B) blocker to determine whether NO antagonizes effects of endothelia-1 on cerebral vascular structure.
The third aim i s to examine effects of hyperhomocysteinemia on cerebral arteriolar structure. The investigators will use cystathionine beta-synthase (CBS) knockout mice to examine the hypothesis that hyperhomocysteinemia produces hypertrophy of cerebral arterioles. The investigators also will examine effects of hypertension induced with a NOS inhibitor in CBS knockout mice to determine whether hyperhomocysteinemia exacerbates structural changes that occur in cerebral blood vessels during chronic hypertension.
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