Integrin Signaling In Vascular Cells

异常的血管平滑肌细胞（SMC）生长和迁移有助于高血压， 动脉粥样硬化和再狭窄。SMC功能由复杂的调节机制控制， 部分由与细胞外基质的相互作用控制。整合素，主要的受体， 细胞外基质激活粘附依赖性信号传导途径并与生长相互作用 因子和G蛋白偶联受体影响细胞功能。本申请的目的是 了解整合素α V β 3依赖性信号传导如何影响SMC生长和迁移。我们 观察到用β 3-整联蛋白的抗体抑制剂治疗的野生型小鼠，但没有 β 3-整合素缺陷（β 3-/-）小鼠，保护内膜增生的发展， 已经发现了培养的野生型和β 3-/-SMC的特性差异，这可能解释了我们的研究。 体内观察。基于我们的初步数据，我们假设整合素α V β 3- 依赖性细胞内信号传导正、负调节SMC的生长和迁移， 在刺激和静止的SMC中存在不同的通路。拟议的研究将利用遗传， 药理学和RNA干扰技术靶向整合素α V β 3， SMC功能的细胞和动物模型。首先，我们将确定α V β 3依赖的途径， 刺激SMC。我们的初步数据表明，α V β 3作为一个分子开关， 调节Rho家族GT3和控制粘着斑组装。我们将描述机制 负责GTTT监管。其次，根据我们的初步数据，我们已经确定了一个角色， α V β 3在细胞静止期下调p38 MAPK中的作用。我们将使用p38 MAPK 通路作为模型，以了解α V β 3依赖性通路如何促进SMC 安静第三，我们将描述α V β 3对培养的细胞的生理反应的贡献。 血管和成熟的动脉损伤小鼠模型。这些结果将提供具体的见解 SMC α V β 3在再狭窄和动脉粥样硬化中的作用，可能具有广泛的意义。 用于了解α V β 3整合素在血管生成、骨质疏松症和其他疾病中的功能。

Abnormal vascular smooth muscle cell (SMC) growth and migration contributes to hypertension, atherosclerosis, and restenosis. SMC function is controlled by complex regulatory mechanisms, which are governed in part by interactions with the extracellular matrix. Integrins, the predominant receptors for the extracellular matrix, activate adhesion-dependent signaling pathways and cross-talk with growth factor and G-protein coupled receptors to influence cellular functions. The objective of this application is to understand how integrin alphaVbeta3-dependent signaling influences SMC growth and migration. We observed that wild-type mice treated with an antibody-inhibitor of beta3-integrins, but not beta3-integrin-deficient (beta3-/-) mice, were protected from the development of intimal hyperplasia and have found differences in the properties of cultured wild-type and beta3-/- SMCs that may account for our in vivo observations. Based on our preliminary data, we hypothesize that integrin alphaVbeta3- dependent intracellular signaling positively and negatively regulates SMC growth and migration thorugh distinct pathways in stimulated and quiescent SMCs. The proposed studies will utilize genetic, pharmacologic, and RNA interference techniques to target integrin alphaVbeta3 in well-characterized cellular and animal models of SMC function. First, we will identify alphaVbeta3-dependent pathways in stimulated SMCs. Our preliminary data indicates that alphaVbeta3 serves as a molecular switch to regulate Rho Family GTPase and control focal adhesion assembly. We will delineate the mechanism(s) responsible for GTPase regulation. Second, based on our preliminary data, we have identified a role for alphaVbeta3 in downregulation of p38MAPK during cellular quiescence. We will use the p38 MAPK pathway as a model to understand how alphaVbeta3-dependent pathways contribute to SMC quiescence. Third, we will delineate the contribution of alphaVbeta3 to physiologic responses in cultured vessels and well-established mouse models of arterial injury. These results will provide specific insights into the function of SMC alphaVbeta3 in restenosis and atherosclerosis and may have broad implications for understanding alphaVbeta3 integrin function in angiogenesis, osteoporosis, and other disorders.