STRUCTURE AND FUNCTION OF CEREBRAL BLOOD VESSELS IN HYPERHOMOCYSTEINEMIA

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Hyperhomocysteinemia is now recognized as a prevalent risk factor for cerebrovascular disease. Despite strong clinical correlations between hyperhomocysteinemia and carotid intimal thickening and stroke, little is known about effects of hyperhomocysteinemia on vascular structure or function in cerebral blood vessels. Emerging evidence suggests that hyperhomocysteinemia increases oxidative stress, and that homocysteine- induced production of superoxide may be a major mechanism for impairment of vasodilation mediated by endothelium-derived nitric oxide. Most of the evidence to support5 this hypothesis has been derived from studies performed in vitro, however, and no studies have been performed to definitively test this hypothesis in vivo. We have developed novel genetic and dietary approaches to produce hyperhomocysteinemia in mice, and we have demonstrated that moderate hyperhomocysteinemia produces endothelial dysfunction and hypertrophy in cerebral arterioles. We now propose to use these murine models to examine mechanisms of impairment and vascular structure and function in the cerebral circulation. The overall goal of this project is to test the hypothesis that hyperhomocysteinemia produces vascular dysfunction and changes in structure in the cerebral circulation through a mechanism that involves superoxide. A key aspect of our experimental design is that vascular effects of altered expression of superoxide dismutase (SOD) will be examined in hyperhomocystemic mice. In Aim 1, we will test the hypothesis that endothelial function in the carotid artery and cerebral arterioles is impaired, and levels of superoxide are increased, during hyperhomocysteinemia, and examine the role of folate in this impairment. In Aim 2, we will test the hypothesis that superoxide is a key mediator of endothelial dysfunction in the cerebral circulation during hyperhomocysteinemia in mice, and whether over- expression of SOD protects from dysfunction. In Aim 3, we will test the hypothesis that superoxide contributes to cerebral vascular hypertrophy during hyperhomocysteinemia.