PHENOTYPIC CONSEQUENCES OF VASCULAR OXIDANT STRESS

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During the past several years, it has become apparent that both endothelial and vascular smooth muscle cells produce superoxide (.O2-) and other reactive oxygen species. Research from our laboratory has shown that in certain disease processes, production of .02- decrease the biological effects of endothelium-derived nitric oxide (NO.). The enzyme systems involved in this process remain incompletely defined and the consequences of alterations of rates of production of reactive oxygen species in the vessel wall are not fully understood. The research planned will examine several aspects of vascular oxygen radical production. Recent work by Dr. Griendling, the director of project 1 in this program project grant, has suggested that p22phox plays an important role in function of a membrane- bound NADH/NADPH-dependent oxidase. In collaboration with Dr. Griendling, we have shown that expression of this portion of the oxidase is increased in the setting of angiotensin II-induced hypertension. Studies are designed to examine the effect of both over expression and inhibition of expression of p22phox on vascular reactivity and blood pressure in transgenic mice. We have recently shown that a significant proportion of angiotensin II-induced hypertension is due to an increase in vascular .02- production. Studies will be performed to determine if this effect is dependent on 02-interacting with NO., or if this phenomena can occur in mice lacking endothelial cell NO synthase. A final aim will be devoted to understanding a new role of oxygen-derived radicals in activation of matrix metalloproteinases (MMPS). Preliminary data show that reactive oxygen species can directly activate MMP-2 and -9. We plan experiments t further understand the phenomenon and to determine if other, biologically relevant reactive oxygen species can activate MMPs. We will also determine if chronic elevation of circulating angiotensin II, a condition associated with increase in vascular .02 production, is also associated with activation of MMPs in vivo. These studies will involve transgenic and "knockout" mice with specific genetic alterations relative to vascular 02- and NO2. production, and promise to provide new and important information regarding interactions between these important radicals.