Protective Mechanisms In The Cerebral Vascular Wall: Rol

一氧化氮（NO）在脑血管结构和功能中起着重要作用，其生物活性部分取决于其与超氧化物的相互作用。超氧化物在脑损伤模型中的作用已经得到了相当大的关注，但对脑血管壁上的超氧化物的作用却知之甚少。这些研究的总体目标是利用新的方法来研究细胞质超氧化物歧化酶（CuZn-SOD）和线粒体（Mn- SOD）在脑血管壁中的作用。我们提出研究CuZn-SOD在脑血管正常功能中起关键作用的假设。药理方法和基因改造小鼠将被用来改变CuZN-SOD的活性，从而开始确定这种SOD同型的作用。血管紧张素II可能有助于慢性高血压期间血管的氧化应激。利用过表达人肾素和人血管紧张素原（R+/ a +）以及CuZn-SOD的转基因小鼠模型，我们将检验CuZn-SOD的超氧化物和活性对高血压患者颈动脉和脑循环结构和功能的影响。Mn-SOD在内皮中高水平表达，脑动脉比颅外血管表达更多，但Mn-SOD的功能意义尚不清楚。在基础条件下，研究人员提出了Mn-SOD保护脑内皮和血管功能的假说。进一步的实验将检验Mn-SOD在高血糖反应中限制超氧化物和内皮功能障碍的假设，高血糖会增加线粒体中的超氧化物。Mn-SOD在sod中是独特的，在氧化应激下Mn-SOD的表达增加。因此，我们还将研究Mn-SOD上调的假设，并限制响应于脂多糖（内毒素）的超氧化物和血管功能障碍的增加，脂多糖（内毒素）是一种在血管壁产生氧化应激的炎症模型。因此，现代分子方法将用于确定正常情况下和高血压、炎症和糖尿病模型下CuZn-和Mn-SOD在脑血管中的作用。这些研究可能会进一步深入了解超氧化物和sod在脑血管生物学中的作用，以及被认为是颈动脉疾病、脑血管功能障碍和中风的血管功能障碍机制。

Nitric oxide (NO) plays a major role in cerebral vascular structure and function and the bioactivity of NO depends, in part, on its interaction with superoxide. The role of superoxide in models of brain injury has received considerable attention, but the role of superoxide within the wall of cerebral blood vessels is poorly understood. The overall goal of these studies is to utilize novel approaches to examine the role of cytosolic superoxide dismutase (CuZn-SOD) and mitochondrial (Mn- SOD) within the cerebral vascular wall. Studies are proposed to examine the hypothesis that CuZn-SOD plays a critical role in normal function of cerebral blood vessels. Pharmacological approaches and genetically- altered mice will be used to alter activity of CuZN-SOD and thus begin to define the role of this isoform of SOD. Angiotensin II may contribute to oxidative stress in blood vessels during chronic hypertension. Using a transgenic mouse model that over-expresses human renin and human angiotensinogen (R+/A+) as well as CuZn-SOD, we will examine the hypothesis that superoxide and activity of CuZn-SOD influence structure and function in carotid artery and cerebral circulation during hypertension Mn-SOD is expressed in high levels in endothelium and cerebral arteries express more Mn-SOD than extracranial blood vessels, but the functional significance of Mn-SOD is not known. Studies are propose to examine the hypothesis that Mn-SOD protects cerebral endothelium and vascular function under basal conditions. Additional experiments will examine the hypothesis that Mn-SOD limits superoxide and endothelial dysfunction in response to hyperglycemia, which increases superoxide in mitochondria. Mn-SOD is unique among the SODs in that expression of Mn-SOD is increased in response to oxidative stress. Thus, we will also examine the hypothesis that Mn-SOD is up-regulated and limits increases in superoxide and vascular dysfunction in response to lipopolysaccharide (endotoxin), a model of inflammation that generates oxidative stress in the vessel wall. Thus, modern molecular approaches will be used to define the role of CuZn- and Mn-SOD in cerebral blood vessels under normal conditions and in models of hypertension, inflammation, and diabetes. These studies may provide greater insight into the role of superoxide and SODs in cerebral vascular biology as well as mechanisms of vascular dysfunction believed to contribute to carotid artery disease, cerebral vascular dysfunction, and stroke.