ALCOHOL REGULATION OF SMOOTH MUSCLE MIGRATION AND GROWTH

描述（改编自申请人的摘要）：流行病学研究表明，适度饮酒或心血管疾病如中风、高血压和冠状动脉疾病（CAD）的发病率具有显著的保护作用，这些疾病是西方世界大多数死亡的原因。此外，体内动物研究表明乙醇对球囊损伤后新生内膜形成具有抑制作用。机械力诱导的动脉平滑肌细胞（SMC）增殖和迁移是两个不同的过程，在高血压、动脉粥样硬化和动脉对损伤的反应的发病机制中的新生内膜形成中发挥重要作用。几项研究提供了令人信服的证据，丝裂原活化蛋白激酶（MAPK）和尿激酶纤溶酶原激活物（uPA），纤溶酶原激活物抑制剂（派-1），基质金属蛋白酶（MMP）在调节SMC的生长和迁移的作用，分别。初步的体外数据表明，在没有内皮细胞的情况下，由于脉动流增加而导致的脉压增加诱导SMC增殖、迁移和MAPK信号传导。此外，乙醇，在生理浓度下，抑制压力和血清诱导的SMC迁移的增加，通过抑制SMC MAPK信号传导，uPA和MMP表达模拟的效果。此外，乙醇抑制血清刺激的MAPK信号传导和SMC的生长，这一作用也是使用特异性MAPK抑制剂模拟的。中心假设是，乙醇在生理浓度下，发挥其对心血管疾病的保护作用，部分是通过抑制压力诱导的SMC增殖和迁移的增加，通过减少这些细胞中的MAPK信号传导。这个最初的独立研究项目提出定义乙醇对脉压诱导的SMC信号传导、生长和迁移变化的影响。利用一种新的灌注跨毛细血管培养系统，使内皮细胞和血管平滑肌细胞长期暴露于生理剪切应力和脉压下（脉动流），研究者将确定乙醇对（i）脉压诱导的SMC增殖和迁移增加，（ii）脉压诱导的SMC MAPK、uPA、MMP变化，派-1和TIMP信号和（iii）MAPK信号在调节脉压诱导的uPA，MMP，TIMP和派-1表达的变化和随后的SMC迁移和增殖的变化中的作用。由于心血管疾病并发症的死亡率如此之高，因此破译物质预防心血管疾病的机制显然具有重大的临床重要性和意义。因此，确定乙醇在改善机械力诱导的SMC增殖和迁移中的保护作用至关重要，这些过程是新生内膜形成的标志，并且是心血管疾病发展的组成部分。

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.