Integrins in the Endothelial Response to Fluid Shear Stress

描述（由申请人提供）：内皮细胞基因表达和行为受到来自流动血液的流体剪切应力的高度调节。内皮细胞对血流的反应调节血管胚胎发生、正常血管生理和动脉粥样硬化的发展。我们以前的工作确定了一个机械转导复合物PECAM-1，VE-钙粘蛋白和VEGF受体2，驻留在细胞-细胞连接和介导的力在这个系统中的生化信号的转换。PECAM-1似乎是真正的力传感器，VE-钙粘蛋白作为一个适配器，将VEGFR 2带入复合物，VEGFR酪氨酸激酶启动关键的下游信号。这些信号包括整合素转化为高亲和力状态，这导致它们与细胞外基质结合。这些新结合的整合素然后产生信号。与该模型一致，内皮细胞下的细胞外基质严格地调节由流动诱导的信号。特别是，PAK（p21激活激酶）介导的基质特异性的关键方面。本研究旨在阐明机械力传导复合体介导的分子机制，并检测PAK在体内动脉粥样硬化形成中的作用。为了实现这些总体目标，我们将：1）测量跨PECAM-1的力并阐明PECAM-1胞质结构域在机械转导中的作用。2)鉴定通过VE-钙粘蛋白介导衔接子功能的蛋白质相互作用。3)检测PAK缺陷小鼠的血管炎症和动脉粥样硬化形成。公共卫生相关性：动脉粥样硬化是一种慢性动脉炎性疾病。在美国，大约一半的死亡是由心脏病发作、中风或其他与动脉粥样硬化相关的血管事件引起的。虽然危险因素如高脂血症和糖尿病是重要的危险因素，但动脉粥样硬化是在流体流动受到干扰的动脉区域引发和维持的。本计画将探讨动脉中机械传导导致动脉硬化的分子机制。了解流体剪切应力如何诱导血管炎症可能会发现新的药物靶点，这些靶点可能会导致更有效的治疗方法来预防或治疗这些疾病。

DESCRIPTION (provided by applicant): Endothelial cell gene expression and behavior is highly regulated by fluid shear stress from flowing blood. Endothelial responses to flow regulate vascular embryogenesis, normal vascular physiology and development of atherosclerosis. Our previous work identified a mechanotransduction complex consisting of PECAM-1, VE-cadherin and VEGF receptor 2 that resides at cell-cell junctions and mediates conversion of force to biochemical signals in this system. PECAM-1 appears to be the true force transducer, VE-cadherin functions as an adapter that brings VEGFR2 into the complex and the VEGFR tyrosine kinase initiates key downstream signals. These signals include conversion of integrins to high affinity states, which leads to their binding to extracellular matrix. These newly bound integrins then generate signals. Consistent with this model, the extracellular matrix under the endothelial cells critically modulates the signals induced by flow. In particular, PAK (p21-activated kinase) mediates critical aspects of this matrix specificity. The current project aims to elucidate the molecular mechanism for transduction by the junctional mechanotransduction complex and to test the role of PAK in atherogenesis in vivo. To achieve these overall goals we will: 1) measure forces across PECAM-1 and elucidate the role of the PECAM-1 cytoplasmic domain in mechanotransduction. 2) identify the protein interactions that mediate adapter function by VE-cadherin. 3) examine vascular inflammation and atherogenesis in PAK-deficient mice. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a chronic inflammatory disease of arteries. Approximately half of all deaths in the United States are caused by heart attacks, strokes or other vascular events associated with atherosclerosis. While risk factors such as hyperlipidemia and diabetes are important risk factors, atherosclerosis is initiated and maintained at regions of arteries that are subject to disturbances in fluid flow. This project will investigate the molecular mechanisms of mechanotransduction in arteries that leads to atherosclerosis. Understand how fluid shear stress induces vascular inflammation is likely to identify new drug targets that may lead to more effective therapies to prevent or treat these diseases.