Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase.

Abstract

Increased numbers of platelet-derived growth factor beta receptors betaPPDGFRs) on neovascular endothelial cells is a common occurrence in several pathological conditions including wound healing, inflammation, and glioma tumorigenesis. Here we sought to test the biological significance of this by determining whether expression of wild-type betaPDGFR by normal aortic endothelial cells affected the expression of the vascular endothelial growth factor (VEGF), a critical angiogenesis regulator and mitogen for such cells. The results showed that PDGF could increase transcription and secretion of VEGF by betaPDGFR-expressing endothelial cells. Moreover, we further demonstrated a requirement for the activation of phosphatidylinositol 3-kinase (PI3K) in this response by using chemical inhibitors of PI3K, mutant PDGFR, and dominant-negative PI3K. These studies suggest a novel mechanism by which PDGF induces VEGF expression in endothelial cells, define VEGF as a downstream target for PI3K, and invoke a role for PI3K in angiogenesis.