Two provocative concepts have recently emerged in relation to mechanisms that contribute to altered cerebral vascular structure during chronic hypertension. First, superoxide, and its regulation by superoxide dismutase(s) (SOD), may play a critical role in regulating vascular structure by interacting with nitric oxide and by participating in cellular signaling and gene regulation. Second, the renin-angiotensin system may play an important role in regulating vascular structure both by generating superoxide and by directly activating specific receptors. The overall objective of this proposal is to utilize novel molecular approaches to examine the roles of superoxide and the renin-angiotensin system in altered cerebral vascular structure in chronic hypertension. The proposed studies address two specific aims.
The first aim i s to clarify the influence of superoxide and SOD on cerebral vascular hypertrophy in chronic hypertension. To test the hypothesis that oxidative stress during chronic hypertension may contribute to cerebral vascular hypertrophy, effects of pressure-overload (induced by transverse aortic banding) will be examined using in vivo methods to assess vascular mechanics, histological methods to define hypertrophy, and biochemical methods to quantitate superoxide levels in carotid arteries and cerebral arterioles of genetically-altered mice that are deficient in the NADPH oxidase subunit, gp91phox, and that overexpress CuZn-SOD. Cerebral vessels also will be examined in these genetically- altered mice with arteriovenous fistulae to test the hypothesis that oxidative stress may contribute to cerebral vascular hypertrophy during increases in arterial pulse pressure, independently of increases in mean pressure. These studies will be among the first to use in vivo approaches to explore the influence of superoxide on vascular structure.
The second aim i s to examine the role of angiotensin II in cerebral vascular remodeling during chronic hypertension. Vascular remodeling (defined as reduction in external diameter) plays an important role in hemodynamic alterations associated with essential hypertension in humans. Genetically altered mice that overexpress human renin (R+) and human angiotensinogen (A+) will be used to test the hypothesis that angiotensin II contributes to remodeling of cerebral arterioles independently of increases in arterial pressure. In addition, R+/A+ mice that are deficient in gp91phox will be generated to test the hypothesis that remodeling of cerebral arterioles in response to overproduction of angiotensin II may depend, at least partly, on the generation of superoxide. Finally, R+/A+ mice will be treated with blockers of angiotensin II type 1 and type 2 receptors to examine the hypothesis that remodeling of cerebral arterioles may be mediated by activation of one or both of these receptor types. These studies should provide important new insight into the mechanisms of vascular remodeling. ? ? ?
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