Mechanisms of neovascularization in response to ischemia

描述(由申请人提供)：对缺血作出反应的新生血管是一个重要的修复过程，在慢性胆固醇升高的情况下，这一过程严重受损。治疗性新生血管试验显示，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形成的影响的信息很少。动脉形成是指在动脉网络之间形成桥梁的侧支血管向外重塑，对于恢复血液灌流至 闭塞后的缺血组织。侧支重构是由血液动力学力量突然增加，特别是剪切力的增加，导致通过侧支的流量急剧增加所致。这种剪切力的增加是通过在内皮细胞(ECs)中表达的机械感觉蛋白来感受的，这些蛋白启动了诱导细胞增殖和炎症等过程的信号转导通路。尽管在使用小分子和基因治疗方法增加缺血时的侧支生长和血流灌注恢复方面做出了重大努力，但结果在很大程度上令人失望，这突显了了解推动动脉形成的分子机制的研究的重要性。我们小组最近发表的工作，结合本申请中提供的初步观察，确定信号蛋白适配器蛋白Src同源蛋白和胶原蛋白(Shc)是新生血管的重要调节因子。为了更好地了解Shc在新生血管中的作用，我们提出了三个相互关联的目标。目的1确定Shc在高胆固醇血症环境中对缺血反应的新生血管中的作用。目的2在体外明确侧支血流动力学条件下，确定Shc在内皮细胞机械转导中的作用。目标3将确定Shc中促进新生血管的分子决定因素。这项建议中提出的实验将有助于我们理解动脉形成和侧支重构的分子机制。为了开发外周血管疾病、动脉硬化和伤口愈合等疾病的治疗策略，需要阐明一些调控缺血后新生血管的信号。

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.