EFFECTS OF HYPERTENSION AND HYPERHOMOCYSTEINEMIA ON CEREBROVASCULAR FUNCTION

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Chronic hypertension is a major risk factor for carotid artery disease and stroke. Studies are ow proposed to use transgenic mice and viral-mediated gene transfer to clarify mechanisms of altered cerebral vascular function in chronic hypertension. Recent evidence suggests that hyperhomocysteinemia also is a major risk factor for carotid artery disease and stroke. Studies are proposed to examine effects of hyperhomocysteinemia on cerebral vascular function. The investigators plan to test the hypothesis that there is endothelia dysfunction in hypertensive double transgenic mice (that overexpress both renin and angiotensinogen), and to examine mechanisms of endothelial dysfunction. Studies are also proposed to determine whether gene transfer of endothelial NO synthase (eNOS) improves vascular responses in stroke-prone spontaneously hypertensive rats (SHRSP) in the basilar and carotid artery. If vascular function improves after gene transfer, this will represent the first "therapeutic" use of gene transfer technology for cerebral blood vessels in an experimental model of a disease state. Cystathionine beta-synthase (CBS) knockout mice develop hyperhomocysteinemia. Studies are planned to determine whether these is endothelia dysfunction in the carotid artery and cerebral arterioles of hyperhomocysteinemic (CBS knockout) mice and, if so, to examine the mechanism. During the past few years, it has become clear that K plus channels are present in cerebral blood vessels, and that activation of K plus channels is an important mechanism of relaxation. Studies are planned to test the hypothesis that responses to an opener of ATP-sensitive (K plus ATP) channels are impaired in hypertensive mice. Studies are proposed to test the hypothesis that, in contrast to K plus ATP channels, functional activity of Ca plusplus minus dependent K plus channels is increased in hypertensive transgenic mice and in SHRSP. Thrombomodulin, which is expressed on endothelium, binds thrombin and activates protein C, a potent anticoagulant. Thromobomodulin activity is inhibited by hyprhomocysteinemia. Studies are proposed to test the hypothesis that thrombomdulin activity is decreased in SHRSP and hypertensive transgenic mice. Impairment of this anticoagulant mechanism might contribute to susceptibility to stroke in hypertension.