Role of Intergrin Signaling in Vascular Remodeling

在缺血性疾病期间，血管内皮细胞对各种刺激做出反应，提示 它们会经历重塑，导致血管通透性和血管生成。在这个项目中，我们将专注于 关于整合素、生长因子受体、酪氨酸激酶和其他细胞黏附分子如何在 在缺血性疾病中影响内皮细胞行为的合作方式。血管内皮细胞 生长因子(VEGF)在缺血性疾病中高表达，并导致双侧血管渗漏 和血管生成，这一过程需要通过血管内皮生长因子受体2(VEGFR2)传递信号。我们有 先前证实，血管内皮生长因子诱导的血管泄漏需要整合素av|35和src家族激酶， 导致VE-钙粘附素介导的细胞-细胞黏附的破坏。然而，相互之间的关系和 这些主要参与者之间的合作仍然鲜为人知。 在这个方案中，我们计划首先描述整合素连接如何影响内皮细胞屏障的破坏。 血管内皮生长因子在缺血性疾病中的诱导作用。接下来，我们将研究基底膜蛋白是如何 在血管内皮生长因子诱导的血管渗漏过程中暴露会吸引和激活血小板，导致有害 微血栓。最后，我们将确定信号素-SA是如何影响血管模式的 抑制整合素的激活，在缺乏血管内皮生长因子的情况下促进血管渗漏，并起到负面作用 血管内皮生长因子诱导的血管生成调节因子。总之，这些研究将有助于从分子水平上洞察 整合素信号如何介导血管内皮生长因子引发的血管事件。 血管渗漏和血管生成是重要的血管重塑事件，具有深远的 对缺血性疾病和炎症的影响。拟议的实验将提供更好的 了解参与这些复合体的血小板和内皮细胞的信号通路 病理生理事件，并将有助于确定新的治疗靶点，以调节血管内皮生长因子诱导 缺血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.