Sphingosine 1-phosphate activates Weibel-Palade body exocytosis

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-␥ 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.nitric oxide ͉ ceramide ͉ endothelial ͉ von Willebrand factor

Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

“…Stxbp5 mRNA was expressed in murine tissues, including lung, spleen, and aorta, as measured by quantitative real-time PCR (qPCR; Figure 1B). Stxbp5 mRNA was also found ECs through discrete signaling pathways (37)(38)(39)(40)(41)(42)(43)(44). However, the detailed mechanisms controlling the endothelial SNARE machinery are not fully known.…”

Angiopoietin-2 Exocytosis Is Stimulated by Sphingosine-1-Phosphate in Human Blood and Lymphatic Endothelial Cells

“…We used dehydro-S1P (dhS1P), a variant of S1P that has only extracellular but not intracellular activity. 26 Treatment of various doses of S1P or dhS1P displayed similar efficacies in stimulating Ang2 exocytosis in ECs ( Figure 3D and supple- mental Figure IV), suggesting that extracellular S1P stimulates Ang2 exocytosis. Extracellular S1P conveys its downstream signaling via plasma membrane GPCR.…”

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…The sphingolipid S1P is similar to thrombin and histamine in that it can potentiate inflammation in the vasculature via exocytosis of vWF and angiopoietin 2 from WPBs (Matsushita et al, 2004;Jang et al, 2009). Matsushita et al (2004) showed that S1P-mediated exocytosis of WPBs occurs in part via PLCg but also involves extracellular calcium, because both PLC inhibitors and calcium-free media blocked S1P-induced secretion of vWF from human aortic ECs.…”

“…Matsushita et al (2004) showed that S1P-mediated exocytosis of WPBs occurs in part via PLCg but also involves extracellular calcium, because both PLC inhibitors and calcium-free media blocked S1P-induced secretion of vWF from human aortic ECs. Given that the receptor was pertussis toxin sensitive, the authors concluded that the S1P must act via a G i -linked receptor (Matsushita et al, 2004).…”

“…Thrombin and histamine stimulation, angiotensin II (Ge et al, 2007), sphingosine-1-phosphate (S1P) (Matsushita et al, 2004), and ATP/ADP (Vischer and Wollheim, 1998) all cause increases in [Ca 2+ ] i via GPCR activation, which is a prime potentiator of exocytosis (Tse et al, 1997), but there is also evidence for extracellular calcium involvement. For example, influx of extracellular calcium via the T-type calcium channels Cav3.1 occurs upon stimulation of pulmonary microvascular ECs with thrombin, resulting in a procoagulant endothelial phenotype (Wu et al, 2003).…”