FUNCTIONAL DISSECTIONS OF VEGF RECEPTORS IN ENDOTHELIUM

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Angiogenesis plays a pivotal role in many important disease processes as well as in normal physiology. It is widely anticipated that modulation of angiogenesis (inhibition in tumors, stimulation in vascular insufficiency) will provide important therapeutic benefit. Many different cytokines and growth factors express angiogenic activity, of these VPF/VEGF stands out because of its potency, selectivity for vascular endothelium, and its consistent overexpression in malignant tumors and in other clinical conditions in which angiogenesis plays an important role. VPF/VEGF acts selectively (though not exclusively) on endothelial cells (EC) by means of two high affinity receptor tyrosine kinases Flt-1 and KDR/Flk-1. Both of these receptors are expressed at increased levels by EC during development and in pathophysiological angiogenesis. Since, most of the endothelial cells express both of the receptors and both of them can homodimerize upon binding to VPF/VEGF, therefore it is difficult to comprehend the molecular function of the individual receptor in the presence of the same ligand. The proposed study aims to dissect the functional aspects and sole responsiveness of these receptors for VPF/VEGF mediated signaling in EC. Chimeric receptors of both KDR and Flt-1 and their respective mutants will be utilized to study signaling pathways responsible for KDR and Flt-1 in vascular endothelial cells. The proposed study thus will delineate the individual role of these two receptors in VPF/VEGF-mediated signaling and will also shed new light on the molecular mechanisms of angiogenesis.