During ischemic disease, endothelial cells lining the blood vessels respond to a variety of stimuli, promptingthem to undergo remodeling leading to vascular permeability and angiogenesis. In this Project, we will focuson how integrins, growth factor receptors, tyrosine kinases, and other cell adhesion molecules function in acooperative manner to influence endothelial cell behavior during ischemic disease. Vascular endothelialgrowth factor (VEGF) becomes highly expressed during ischemic disease and induces both vascular leakand angiogenesis, processes which require signaling through VEGF Receptor 2 (VEGFR2). We havepreviously 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 andcooperation between these key players,remain poorly understood.In this proposal, we plan to first characterize how integrin ligation influences endothelial cell barrier disruptioninduced by VEGF during ischemic disease. Next, we will examine how basement membrane proteinsexposed during VEGF-induced vascular leak attract and activate platelets, leading to deleteriousmicrothrombi. Lastly, we will determine how semaphorin-SA, thought to influence vascular patterning bysuppressing integrin activation, promotes vascular leak in the absence of VEGF, and acts as a negativeregulator of VEGF-induced angiogenesis. Together, these studies will serve to provide molecular insight intohow integrin signaling mediates the vascular events initated by VEGF.Vascular leak and angiogenesis represent significant vascular remodeling events which have a profoundimpact on ischemic disease and inflammation. The proposed experiments will provide a betterunderstanding of the signaling pathways in platelets and endothelial cells involved in these complexpathophysiological events, and will serve to identify new therapeutic targets to regulate VEGF-inducedvascular leak and vascular remodeling following ischemic injury.
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