Studies are proposed to examine effects of chronic hypertension and aging on cerebral blood vessels. The goals are to examine mechanisms and consequences of alterations in cerebral vascular structure and function during chronic hypertension, and to examine mechanisms that may contribute to altered structure and function of cerebral vessels during aging. Several hypotheses will be tested. First, studies are proposed to examine mechanisms by which chronic hypertension alters structure and mechanics of cerebral arterioles. Three hypotheses will be tested using an in vivo method to examine vascular distensibility, and morphometric methods to examine vascular composition. First, normotensive rats will be treated chronically with a blocker of nitric oxide production to test the hypothesis that endothelium-derived relaxing factors may contribute to hypertrophy and remodeling of cerebral arterioles during chronic hypertension. Second, normotensive Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) will be treated chronically with a cyclooxygenase inhibitor and a thromboxane A2 receptor antagonist to examine the hypothesis that a cyclooxygenase-dependent, endothelium-derived constricting factor may contribute to hypertrophy with increases in distensibility and remodeling of cerebral arterioles in SHRSP. Finally, to test the hypothesis that heparin-like glycosaminoglycans may play a role in alterations of cerebral vascular structure and mechanics, heparin will be infused chronically in WKY and SHRSP. Second, studies are proposed to examine consequences of altered structure and mechanics to cerebral vascular function during chronic hypertension. In one study, the hypothesis that large, as well as small, cerebral vessels contribute to enhanced autoregulatory constriction in chronic hypertension will be examined by determining resistance of large and small cerebral vessels in WKY and SHRSP during acute increases in arterial pressure. In another study, a newly developed in vitro method will be used to test the hypothesis that both remodeling of cerebral arterioles and reduced distensibility of large cerebral arteries may be important mechanisms by which structural changes alter cerebral vascular responses during chronic hypertension. Third, smooth muscle in cerebral arterioles undergoes atrophy during aging with a reduction in arteriolar distensibility. Studies are planned to examine the hypotheses that alterations in structure and mechanics of cerebral arterioles during aging may be associated with, and perhaps due in part to, 1) reduction in arteriolar pulse pressure and dP/dt, 2) prolonged exposure of the vessel wall to oxygen-derived free radicals, and 3) increases in heparin-like glycosaminoglycans in extracellular matrix of the arteriolar wall. The studies have considerable potential to clarify the mechanisms through which chronic hypertension and aging modify cerebral vascular structure and function. In addition, the studies should provide additional insight into the interaction of structure and function in the vessel wall.
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