Protective Mechanisms In The Cerebral Vascular Wall: Rol

一氧化氮(NO)在脑血管结构和功能中起重要作用，其生物活性在一定程度上依赖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受到了相当大的关注，但对脑血管壁中超氧化物的作用知之甚少。这些研究的总体目标是利用新的方法来研究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。有人建议进行研究，以检验铜锌超氧化物歧化酶在脑血管正常功能中起关键作用的假设。药理学方法和基因改变的小鼠将被用来改变铜锌超氧化物歧化酶的活性，从而开始确定这种超氧化物歧化酶的异构体的作用。血管紧张素II可能参与慢性高血压时血管内的氧化应激。利用过表达人肾素和人血管紧张素原(R+/A+)和CuZn-SOD的转基因小鼠模型，我们将验证这样一种假说，即在高血压期间，CuZn-SOD的超氧化物歧化和活性影响颈动脉和脑循环的结构和功能，而脑动脉内皮细胞和脑动脉表达的Mn-SOD比颅外血管高，但其功能意义尚不清楚。研究表明，在基础状态下，锰-超氧化物歧化酶具有保护脑血管内皮和血管功能的作用。更多的实验将检验这一假设，即锰-超氧化物歧化酶限制超氧化物和内皮功能障碍，以应对高血糖，这增加了线粒体中的超氧化物。在超氧化物歧化酶中，锰-超氧化物歧化酶的独特之处在于，在氧化应激下，锰-超氧化物歧化酶的表达增加。因此，我们还将检验这一假说，即在内毒素(一种在血管壁上产生氧化应激的炎症模型)的反应下，Mn-SOD上调并限制超氧化物歧化酶和血管功能障碍的增加。因此，现代分子方法将被用来确定在正常情况下以及在高血压、炎症和糖尿病模型中铜锌和锰-超氧化物歧化酶在脑血管中的作用。这些研究可能会更深入地了解超氧化物歧化酶和超氧化物歧化酶在脑血管生物学中的作用，以及血管功能障碍的机制，这些机制被认为是导致颈动脉疾病、脑血管功能障碍和中风的原因。

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.