Vascular endothelial growth factor regulation of Weibel-Palade-body exocytosis.
Vascular endothelial growth factor (VEGF) not only regulates angiogenesis, vascular permeability, and vasodilation but also promotes vascular inflammation. However, the molecular basis for the proinflammatory effects of VEGF is not understood. We now show that VEGF activates endothelial cell exocytosis of Weibel-Palade bodies, releasing vasoactive substances capable of causing vascular thrombosis and inflammation. VEGF triggers endothelial exocytosis in part through calcium and phospholipase C-gamma (PLC-gamma) signal transduction. However, VEGF also modulates endothelial cell exocytosis by activating endothelial nitric oxide synthase (eNOS) production of nitric oxide (NO), which nitrosylates N-ethylmaleimide sensitive factor (NSF) and inhibits exocytosis. Thus, VEGF plays a dual role in regulating endothelial exocytosis, triggering pathways that both promote and inhibit endothelial exocytosis. Regulation of endothelial exocytosis may explain part of the proinflammatory effects of VEGF.
Matsushita
Kenji
K
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yamakuchi
Munekazu
M
Morrell
Craig N
CN
Ozaki
Michitaka
M
O'Rourke
Brian
B
Irani
Kaikobad
K
Lowenstein
Charles J
CJ
D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D005089:Exocytosis / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D052066:N-Ethylmaleimide-Sensitive Proteins; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020302:Weibel-Palade Bodies / Q000187:drug effects* / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; D014841:von Willebrand Factor; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin; D052066:N-Ethylmaleimide-Sensitive Proteins; D002118:Calcium