Alcohol Regulation of Smooth Muscle Migration and Growth

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DESCRIPTION (provided by applicant): Epidemiological studies associate moderate alcohol consumption with a reduced incidence of cardiovascular disease. Moreover, animal studies demonstrate an inhibitory effect of ethanol ol the development and progression of atherosclerotic lesions and on neointimal formation following balloon injury. However, the precise mechanisms mediating these beneficial effects are unknown. Mechanical force-induced arterial smooth muscle cell (SMC) proliferation, apoptosis and migration are distinct processes that play an important role in the pathogenesis of atherosclerosis and the arterial response to injury. Several studies support a role for proteases, (urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMPs) and their inhibitors), in regulating SMC proliferation, apoptosis and migration. Indeed, we have previously demonstrated that pulse pressure-induced SMC migration is dependent on uPA and MMPs. Furthermore, SMC migration and replication is impaired in MMP-9 -/- arteries following a denuding injury. Integrins participate in several signaling pathways and are key mediators of mechanical force-induced events in SMC. Of particular notice as a mechano transducer and regulator of SMC function is integrin receptor alpha-v-beta3. Interestingly, recent studies have implicated alpha-v-beta3 in the control of MMP expression and activity in vascular cells. Our preliminary data also demonstrate an inhibitory effect of ethanol on serum stimulated SMC proliferation and migration in 'static' cultures, and on pulse pressure-stimulated MMP-2 and MMP-9 expression and activity. Based on these observations and reports in the literature, our central hypothesis is that ethanol exerts its protective effect on cardiovascular disease, in part, by inhibiting vascular SMC migration and proliferation. Specifically, we hypothesize that ethanol controls the migration, proliferation and apoptosis of SMC, and thus vascular remodeling, by modulating mechanical force activated integrin alpha-v-beta3 receptor signaling and subsequent protease expression and activity. Using a perfused transcapillary culture system in conjunction with a Flexercell strain apparatus to expose human SMC to defined, physiologically relevant pulse pressures and cyclic strains, respectively, we propose to define the effects of ethanol on mechanical force-induced SMC growth (proliferation and apoptosis) and migration and to elucidate the signaling mechanisms involved. Because the mortality from the complications of cardiovascular disease is so high, deciphering the mechanism whereby a substance can protect against it is clearly of major clinical importance and significance. Accordingly, it is critical to define the protective role of ethanol in ameliorating mechanical force-induced SMC proliferation, apoptosis and migration, processes which are hallmarks of neointimal formation and which are integral to the development of cardiovascular disease.