Production of reactive oxygen species by blood vessels may contribute to the pathophysiology of atherosclerosis through a variety of mechanisms. Previous studies have focused on the role of reactive oxygen species generated by the endothelium in modulation of vascular function. The investigators have recently shown that superoxide (O2.) levels are increased in vascular smooth muscle cells (SMC) of atherosclerotic compared to normal vessels. The enzymatic sources of SMC O2. in atherosclerosis and its contribution to vascular pathophysiology are not known. The major hypothesis of this project is that generation of O2 by SMC contributes to vascular dysfunction in atherosclerosis. Studies are proposed to examine vessels of a genetic model (ApoE/LDLr deficient mice) and a primate model (cynomolgus monkeys) of atherosclerosis. First, using intact vessels and cultured cells, studies are planned to determine the enzymatic source of O2. in SMC by examining the role of xanthine oxidase, nitric oxide synthase, and NAD(P)H oxidase. Second, studies are planned to determine the potential physiologic importance of SMC O2. and whether levels of O2 can be altered by substances present in the atherosclerotic lesion. The physiologic importance of O2 in SMC from atherosclerotic vessels will be examined by measuring cyclic-GMP in SMC in response to nitric oxide. Studies will determine whether gene transfer of superoxide dismutase to SMC from atherosclerotic vessels improves responsiveness to nitric oxide. In addition, we will examine the role of SMC O2. in atherosclerosis by developing a transgenic model over-expressing superoxide dismutase under the transcriptional control of an SMC-specific SM22alpha promoter. Studies are planned to examine the effects of selective reduction of SMC O2. on the development of vasomoter dysfunction, lesion development, and vascular O2. Studies are proposed to determine whether platelet derived growth factor and angiotensin-II, factors that may be increased in atherosclerosis, augment SMC production of O2. Third, studies are proposed to test the hypothesis that improved vasomoter function during repression of atherosclerosis is associated with reduction in SMC production of O2. Changes in O2. levels will be measured in monkeys after regression of atherosclerosis. The proposed studies are an extension of the novel observation made by the investigators of SMC generation of O2. in atherosclerosis, and may provide findings that alter the view of the role of SMC in atherosclerosis.
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