ALCOHOL REGULATION OF SMOOTH MUSCLE MIGRATION AND GROWTH

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DESCRIPTION (Adapted from Applicant's Abstract): Epidemiological studies demonstrate a significant protective effect of moderate alcohol consumption or the incidence of cardiovascular disorders such as stroke, hypertension and coronary artery disease (CAD) which account for the majority of deaths in the Western world. In addition, in vivo animal studies demonstrate an inhibitory effect of ethanol on neointimal formation following balloon injury. Mechanical force-induced arterial smooth muscle cell (SMC) proliferation and migration are two distinct processes that play an important role in neointimal formation during the pathogenesis of hypertension, atherosclerosis and the arterial response to injury. Several studies have provided compelling evidence for a role of mitogen activated protein kinases (MAPKs) and urokinase plasminogen activators (uPA), plasminogen activator inhibitor (PAI-1), and matrix metalloproteinases (MMP) in regulating SMC growth and migration, respectively. Preliminary in vitro data demonstrate that increases in pulse pressure due to increases in pulsatile flow induces SMC proliferation, migration and MAPK signaling in the absence of endothelial cells. Furthermore ethanol, at physiological concentrations, inhibits pressure- and serum-induced increases in SMC migration, an effect that is mimicked by inhibiting SMC MAPK signaling, uPA and MMP expression. In addition, ethanol inhibits serum-stimulated MAPK signaling and growth of SMC, an effect that is also mimicked using a specific MAPK inhibitor. The central hypothesis is that ethanol at physiological concentrations, exerts its protective effect on cardiovascular disease, in part, by inhibiting pressure-induced increases in SMC proliferation and migration by decreasing MAPK signaling in these cells. This initial independent research project proposes to define the effects of ethanol on pulse pressure induced changes in SMC signaling, growth and migration. Utilizing a novel perfused transcapillary culture system, whereby endothelial and vascular smooth muscle cells can be chronically exposed to physiological shear stress and pulse pressures (pulsatile flow), the investigators will define the dose and temporal effects of ethanol on (i) pulse pressure induced increases in SMC proliferation and migration, (ii) pulse pressure induced changes in SMC MAPK, uPA, MMP, PAI-1 and TIMP signaling and (iii) the role of MAPK signaling in modulating pulse pressure-induced changes in uPA, MMP, TIMP and PAI-1 expression and subsequent changes in SMC migration and proliferation. 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 and migration, processes which are hallmarks of neointimal formation and which are integral to the development of cardiovascular disease.