Vascular endothelial growth factor (VEGF) function is critical for vascular development. However, the molecular events that coordinate vascular development and kidney morphogenesis are unknown. VEGF is expressed in parenchymal cells contiguous to the developing kidney vasculature throughout embryonic life and postnatal life. We showed that VEGF induces vasculogenesis in metanephric organ culture and that VEGF is a chemoattractant providing direction to migrating endothelial cells during renal morphogenesis, suggesting that VEGF is important to establish the spatial organization of the renal vasculature. The molecular basis of the vascular spatial organization in the developing kidney and the function of VEGF in renal epithelial cells are unknown and are the focus of this proposal. The objective of this proposal is to elucidate the mechanisms mediating directional endothelial cell migration during kidney organogenesis and vascularization. Our hypothesis is that VECiF produced by renal epithelial cells generates local concentration gradients providing a chemoattractive cue for endothelial cell migration. We also postulate that VEGF supports the establishment and maintenance of fenestrated endothelial cell phenotype and thereby contributes to the regulation of vascular permeability. To test our hypotheses: 1) we will study the mechanism of directional endothelial cell migration towards embryonic kidneys and examine the function of the VEGF system in renal epithelial cells using migration assays and co-culture models. 2) We will study the downstream signaling mechanisms involved in VEGF-induced directional endothelial cell migration: examine the role of integrins, FAK and MAP kinase mediated signals. 3) We will determine whether VEGF is required for the establishment and maintenance of the fenestrated phenotype of glomerular endotheial cells in vitro and study the signaling mechanisms involved. The proposed experiments should provide fundamental information regarding VEGF-induced directional migration and advance our knowledge of the molecular mechanisms governing vascular spatial organization and renal morphogenesis. Understanding the molecular basis of guidance cues for cell migration should enable us to generate new strategies for diagnosis and treatment of congenital renal abnormalities and cancer.
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