Alcohol Regulation of Smooth Muscle Migration and Growth

描述（由申请人提供）： 流行病学研究将适度饮酒与心血管疾病发病率降低联系起来。此外，动物研究表明乙醇对动脉粥样硬化病变的发展和进展以及球囊损伤后的新生内膜形成具有抑制作用。然而，介导这些有益效果的确切机制尚不清楚。机械力诱导的动脉平滑肌细胞（SMC）增殖、凋亡和迁移是动脉粥样硬化发病机制和动脉对损伤的反应中的重要过程。一些研究支持蛋白酶（尿激酶纤溶酶原激活物（uPA）和基质金属蛋白酶（MMPs）及其抑制剂）在调节SMC增殖、凋亡和迁移中的作用。事实上，我们以前已经证明，脉压诱导的SMC迁移依赖于uPA和MMPs。此外，剥脱损伤后MMP-9 -/-动脉中的SMC迁移和复制受损。整合素参与多种信号通路，是SMC中机械力诱导事件的关键介质。特别值得注意的是，作为SMC功能的机械换能器和调节剂的是整联蛋白受体α-v-β 3。有趣的是，最近的研究表明α-v-β 3参与了血管细胞中MMP表达和活性的控制。我们的初步数据还表明，乙醇对血清刺激的SMC增殖和迁移的抑制作用，在“静态”的文化，和脉压刺激的MMP-2和MMP-9的表达和活性。基于这些观察结果和文献报道，我们的中心假设是乙醇对心血管疾病发挥保护作用，部分是通过抑制血管SMC迁移和增殖。具体而言，我们假设乙醇通过调节机械力激活的整合素α-v-β 3受体信号传导和随后的蛋白酶表达和活性来控制SMC的迁移、增殖和凋亡，从而控制血管重塑。使用灌注transcapillary培养系统与Flexercell应变装置，以暴露人SMC定义，生理相关的脉冲压力和周期应变，分别，我们建议定义乙醇对机械力诱导的SMC生长（增殖和凋亡）和迁移的影响，并阐明所涉及的信号转导机制。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、凋亡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 (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.