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之间存在很强的临床相关性，但关于高同型半胱氨酸血症对脑血管中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增加氧化应激，并且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受损的主要机制。支持这一假设的大多数证据5来自体外研究，但是，尚未进行任何研究来明确检验体内这一假设。我们已经开发了新的遗传和饮食方法来产生高同型半胱氨酸血症的小鼠，我们已经证明，中度高同型半胱氨酸血症产生内皮功能障碍和肥大的脑小动脉。我们现在建议使用这些小鼠模型来研究脑循环中的损伤机制和血管结构和功能。该项目的总体目标是检验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变化的假设。我们的实验设计的一个关键方面是，超氧化物歧化酶（SOD）的表达改变的血管效应将在高同型半胱氨酸小鼠中进行检查。在目的1中，我们将测试的假设，即在颈动脉和脑小动脉内皮功能受损，超氧化物水平增加，在高同型半胱氨酸血症，并检查叶酸在这种损害的作用。在目的2中，我们将测试超氧化物是小鼠高同型半胱氨酸血症期间脑循环中内皮功能障碍的关键介质的假设，以及SOD的过度表达是否保护功能障碍。在目标3中，我们将检验超氧化物在高同型半胱氨酸血症期间促进脑血管肥大的假设。

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.