VEGF effect on vascular permeability is mediated by synthesis of platelet-activating factor.
Vascular endothelial growth factor (VEGF), a protein synthesized and secreted by a variety of normal and neoplastic cells, serves as an endothelial cell-specific mitogen and a potent angiogenic factor. Intradermal injection of VEGF increases vascular permeability, a critical event in inflammation and angiogenesis. We sought to identify which tissues are responsive to the inflammatory effect of VEGF, to investigate the mechanisms by which VEGF increases vascular permeability, and to establish whether mediators of inflammation such as platelet-activating factor (PAF) play a role in this regard. Intravenous injection of VEGF (0.001-0.1 nmol/kg) into rats induced dose-dependent protein extravasation in vascular beds of certain tissues up to 177% over control levels. In some tissues, the elevation in vascular permeability in vivo was abolished completely by selective PAF-receptor antagonists. Moreover, VEGF (10(-11) to 10(-9) M) was found to increase PAF synthesis in cultured bovine aortic endothelial cells up to 20-fold. Our results suggest that VEGF increases vascular permeability by inducing PAF synthesis.
Sirois
M G
MG
Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Edelman
E R
ER
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004224:Diterpenes; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D046934:Ginkgolides; D007275:Injections, Intravenous; D007783:Lactones / Q000494:pharmacology; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology*; D008934:Mitogens / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000096:biosynthesis* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D001798:Blood Proteins; D004224:Diterpenes; D016228:Endothelial Growth Factors; D005343:Fibrinolytic Agents; D046934:Ginkgolides; D007783:Lactones; D008222:Lymphokines; D008934:Mitogens; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C039351:platelet activating factor receptor; C045856:ginkgolide B