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.
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