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Blood, 1 January 2005, Vol. 105, No. 1, pp. 207-214.
Prepublished online as a Blood First Edition Paper on September 2, 2004; DOI 10.1182/blood-2004-04-1519.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Vascular endothelial growth factor regulation of Weibel-Paladebody exocytosis
Kenji Matsushita,
Munekazu Yamakuchi,
Craig N. Morrell,
Michitaka Ozaki,
Brian O'Rourke,
Kaikobad Irani, and
Charles J. Lowenstein
From the Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD; the Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD; and the Department of Comparative Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD.
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- (PLC- ) 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.

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