Role of Intergrin Signaling in Vascular Remodeling

在缺血性疾病期间，血管内衬的内皮细胞对各种刺激作出反应，促使血管内皮细胞的生长和分化。 它们经历重塑，导致血管渗透性和血管生成。在本项目中，我们将重点 关于整合素、生长因子受体、酪氨酸激酶和其他细胞粘附分子如何在一个 协同方式影响缺血性疾病期间内皮细胞的行为。血管内皮 在缺血性疾病期间，生长因子（VEGF）变得高度表达， 和血管生成，需要通过VEGF受体2（VEGFR 2）进行信号传导的过程。我们有 之前已经证实VEGF诱导的血管渗漏需要整合素av| 35和Src家族激酶， 导致VE-钙粘蛋白介导的细胞-细胞粘附的破坏。然而，相互关系和 对这些关键角色之间的合作仍然知之甚少。 在这个提议中，我们计划首先描述整合素连接如何影响内皮细胞屏障破坏 在缺血性疾病期间由VEGF诱导。接下来，我们将研究基底膜蛋白如何 在VEGF诱导的血管渗漏过程中暴露，吸引并激活血小板，导致有害的 微血栓最后，我们将确定如何semaphorin-SA，被认为是影响血管图案， 抑制整联蛋白活化，在缺乏VEGF的情况下促进血管渗漏，并作为负调节因子。 VEGF诱导的血管生成的调节因子。总之，这些研究将有助于提供分子洞察力， 整合素信号传导如何介导VEGF引发的血管事件。 血管渗漏和血管生成代表重要的血管重塑事件，其具有深刻的临床意义。 对缺血性疾病和炎症影响。这些实验将提供一个更好的 了解血小板和内皮细胞参与这些复杂的信号通路 病理生理事件，并将用于确定新的治疗靶点，以调节VEGF诱导的 缺血性损伤后的血管渗漏和血管重塑。

During ischemic disease, endothelial cells lining the blood vessels respond to a variety of stimuli, prompting them to undergo remodeling leading to vascular permeability and angiogenesis. In this Project, we will focus on how integrins, growth factor receptors, tyrosine kinases, and other cell adhesion molecules function in a cooperative manner to influence endothelial cell behavior during ischemic disease. Vascular endothelial growth factor (VEGF) becomes highly expressed during ischemic disease and induces both vascular leak and angiogenesis, processes which require signaling through VEGF Receptor 2 (VEGFR2). We have previously established that VEGF-induced vascular leak requires integrin av|35 and Src family kinases, leading to the disruption of VE-cadherin-mediated cell-cell adhesion. However, the interrelationships and cooperation between these key players,remain poorly understood. In this proposal, we plan to first characterize how integrin ligation influences endothelial cell barrier disruption induced by VEGF during ischemic disease. Next, we will examine how basement membrane proteins exposed during VEGF-induced vascular leak attract and activate platelets, leading to deleterious microthrombi. Lastly, we will determine how semaphorin-SA, thought to influence vascular patterning by suppressing integrin activation, promotes vascular leak in the absence of VEGF, and acts as a negative regulator of VEGF-induced angiogenesis. Together, these studies will serve to provide molecular insight into how integrin signaling mediates the vascular events initated by VEGF. Vascular leak and angiogenesis represent significant vascular remodeling events which have a profound impact on ischemic disease and inflammation. The proposed experiments will provide a better understanding of the signaling pathways in platelets and endothelial cells involved in these complex pathophysiological events, and will serve to identify new therapeutic targets to regulate VEGF-induced vascular leak and vascular remodeling following ischemic injury.