Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase.
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.
Wang
D
D
Ludwig Institute for Cancer Research, University of California-San Diego, 92093-0660, USA. dbwang@ucsd.edu
Huang
H J
HJ
Kazlauskas
A
A
Cavenee
W K
WK
D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019869:Phosphatidylinositol 3-Kinases