STRUCTURE AND FUNCTION OF CEREBRAL BLOOD VESSELS IN HYPERHOMOCYSTEINEMIA

高同型半胱氨酸血症现在被认为是脑血管疾病的一个普遍危险因素。尽管高同型半胱氨酸血症与颈动脉内膜增厚和中风有很强的临床相关性，但对高同型半胱氨酸血症对脑血管血管结构或功能的影响知之甚少。新出现的证据表明，高同型半胱氨酸血症会增加氧化应激，而同型半胱氨酸诱导的超氧化物的产生可能是内皮源性一氧化氮介导的血管舒张功能受损的主要机制。然而，支持这一假设的大多数证据都来自体外研究，没有研究在体内明确地验证这一假设。我们已经开发了新的遗传和饮食方法来产生小鼠高同型半胱氨酸血症，我们已经证明中度高同型半胱氨酸血症会产生内皮功能障碍和脑小动脉肥大。我们现在建议使用这些小鼠模型来检查脑循环损伤和血管结构和功能的机制。该项目的总体目标是验证高同型半胱氨酸血症通过涉及超氧化物的机制产生血管功能障碍和脑循环结构改变的假设。我们实验设计的一个关键方面是，超氧化物歧化酶（SOD）表达改变对血管的影响将在高同型系统小鼠中进行研究。在Aim 1中，我们将检验高同型半胱氨酸血症期间颈动脉和脑小动脉内皮功能受损，超氧化物水平升高的假设，并检查叶酸在这种损害中的作用。在Aim 2中，我们将验证超氧化物是小鼠高同型半胱氨酸血症期间脑循环内皮功能障碍的关键介质的假设，以及超氧化物歧化酶的过度表达是否可以保护功能障碍。在Aim 3中，我们将验证高同型半胱氨酸血症期间超氧化物导致脑血管肥大的假设。

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.