Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

doi:10.1073/pnas.0400185101

Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

Departments of ^*Medicine, ^†Pathology, and ^‡Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved June 16, 2004 (received for review January 9, 2004)

Abstract

Sphingosine 1-phosphate (S1P) not only regulates angiogenesis, vascular permeability and vascular tone, but it also promotes vascular inflammation. However, the molecular basis for the proinflammatory effects of S1P is not understood. We now show that S1P activates endothelial cell exocytosis of Weibel-Palade bodies, releasing vasoactive substances capable of causing vascular thrombosis and inflammation. S1P triggers endothelial exocytosis in part through phospholipase C-γ signal transduction. However, S1P also modulates endothelial cell exocytosis by activating endothelial nitric oxide synthase production of nitric oxide, which inhibits exocytosis. Thus S1P 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 S1P.

Footnotes

↵ § To whom correspondence should be addressed. E-mail: clowenst{at}jhmi.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: S1P, sphingosine-1-phosphate; GPCR, G protein-coupled receptor; PLC, phospholipase C; eNOS, endothelial NO synthase; VWF, von Willebrand factor; DMS, d-erythro-N,N-dimethylsphingosine; TNA-α, tumor necrosis factor α; SNAP, S-nitrosothiolpenicillamine; HAEC, human aortic endothelial cells; l-NAME, N-nitro-l-arginine methyl ester; PTX, pertussis toxin; sP-selectin, soluble P-selectin; PI3-K, phosphatidylinositol 3-kinase.