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.
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