Mechanisms of neovascularization in response to ischemia

描述（由申请方提供）：缺血引起的新生血管形成是一个重要的修复过程，在胆固醇长期升高的情况下会严重受损。治疗性新血管形成试验显示高胆固醇血症患者的反应显著降低;然而，关于高胆固醇血症对动脉生成的影响的信息很少。动脉生成，即形成动脉网络之间桥梁的侧支血管的向外重塑，对于恢复血液灌注以恢复血管的功能至关重要。 闭塞后的缺血组织。侧支重塑是由血液动力学力的突然增加驱动的，特别是剪切应力，这是由通过侧支的流量急剧增加引起的。这种剪切应力的增加由内皮细胞（EC）中表达的机械感觉蛋白感知，其启动诱导诸如细胞增殖和炎症的过程的信号转导途径。尽管在使用小分子和基因治疗方法的缺血背景下，为增加侧支生长和灌注恢复做出了重大努力，但结果在很大程度上令人失望，这强调了了解驱动动脉生成的分子机制的研究的重要性。我们小组最近发表的工作，加上本申请中提供的新生观察结果，鉴定了信号蛋白衔接蛋白Src同源和胶原蛋白（Shc）作为新血管形成的重要调节因子。为了更好地理解Shc在新生血管形成中的作用，提出了三个相互关联的目标。目的1将确定在高胆固醇血症的情况下，Shc在新生血管形成中对缺血反应的作用。目的2将确定Shc的作用，在内皮细胞的机械转导在体外确定侧支血流动力学条件下。目的3将确定促进新生血管形成的Shc分子决定因素。本实验将有助于我们对动脉形成和侧支重建的分子机制的理解。需要阐明调节缺血后新血管形成的一些信号，以便开发用于诸如外周血管疾病、动脉硬化和伤口愈合的疾病的治疗策略。

DESCRIPTION (provided by applicant): Neovascularization in response to ischemia is an important repair process, which is severely compromised in the setting of chronically elevated cholesterol. Therapeutic neovascularization trials have revealed dramatically reduced responses in hypercholesterolemic patients; however, there is little information on the effects of hypercholesterolemia on arteriogenesis. Arteriogenesis, the outward remodeling of collateral vessels that form bridges between arterial networks, is critical for recovery of blood perfusion to the ischemic tissue after occlusion. Collateral remodeling is driven by a sudden increase in hemodynamic forces, especially shear stress, resulting from the drastic increase in flow through collaterals. This increase in shear stress is sensed by mechanosensory proteins expressed in endothelial cells (ECs), which initiate signal transduction pathways that induce processes such as cell proliferation and inflammation. Despite significant efforts to increase collateral growth and perfusion recovery in the setting of ischemia using small molecules and gene therapy approaches, results have been largely disappointing, underscoring the importance of studies on understanding the molecular mechanisms that drive arteriogenesis. Recently published work from our group, coupled with nascent observations provided in this application, identify the signaling protein adaptor protein Src homologous and collagen protein (Shc) as an essential regulator of neovascularization. To better understand the role of Shc in neovascularization, three interrelated aims are proposed. Aim 1 will determine the role of Shc in neovascularization in response to ischemia in the setting of hypercholesterolemia. Aim 2 will determine the role of Shc in endothelial mechanotransduction under defined collateral hemodynamic conditions in vitro. Aim 3 will determine the molecular determinants in Shc that facilitate neovascularization. Experiments proposed in this proposal will contribute to our understanding of molecular mechanisms of arteriogenesis and collateral remodeling. Elucidation of some of the signals that regulate post-ischemic neovascularization is needed in order to develop therapeutic strategies for diseases such as peripheral vascular disease, arteriosclerosis and wound healing.