Sphingosine‐1‐Phosphate and Its Receptors: A Mutual Link between Blood Coagulation and Inflammation

Abstract

Sphingosine-1-phosphate (S1P) is a versatile lipid signaling molecule and key regulator in vascular inflammation. S1P is secreted by platelets, monocytes, and vascular endothelial and smooth muscle cells. It binds specifically to a family of G-protein-coupled receptors, S1P receptors 1 to 5, resulting in downstream signaling and numerous cellular effects. S1P modulates cell proliferation and migration, and mediates proinflammatory responses and apoptosis. In the vascular barrier, S1P regulates permeability and endothelial reactions and recruitment of monocytes and may modulate atherosclerosis. Only recently has S1P emerged as a critical mediator which directly links the coagulation factor system to vascular inflammation. The multifunctional proteases thrombin and FXa regulate local S1P availability and interact with S1P signaling at multiple levels in various vascular cell types. Differential expression patterns and intracellular signaling pathways of each receptor enable S1P to exert its widespread functions. Although a vast amount of information is available about the functions of S1P and its receptors in the regulation of physiological and pathophysiological conditions, S1P-mediated mechanisms in the vasculature remain to be elucidated. This review summarizes recent findings regarding the role of S1P and its receptors in vascular wall and blood cells, which link the coagulation system to inflammatory responses in the vasculature.

Sphingosine‐1‐Phosphate Modulates the Effect of Estrogen in Human Osteoblasts

“…Measurements of S1P in serum indicate that it circulates at concentrations of 500 to 1000 nM, albeit significantly protein bound and in some circumstances released by platelet activation. Carriers of S1P include albumin and apolipoprotein M; in serum, S1P is important in vascular homeostasis and immune cell response . There are precedents for osteoblast‐derived S1P as potentially protecting cancer proliferation, but at present physiological levels of S1P in bone and regulation of its production in vivo are not well characterized.…”

Effects of Aspirin on Endothelial Function and Hypertension

“…1). Sphingosine-1 phosphate is produced via two isoforms of sphingosine kinase (SphK), of which SphK2 is predominant in platelets, and then binds to S1P receptors on endothelial cells and smooth muscle cells [86]. …”

Sphingosine-1-Phosphate (S1P)-Related Response of Human Conjunctival Fibroblasts After Filtration Surgery for Glaucoma

“…33,41,[43][44][45][46][47] Previous reports indicated that S1P concentrations in the blood fluid ranged between 0.2 and 0.9 lM, which is high, but the levels were lower in tissues (0.5-75 pmol/mg), suggesting that S1P is secreted by cells in blood vessel walls or by blood cells. 24,25 Thus, the high S1P concentrations that we observed in this study might have arisen because of bleeding during the operation. S1P may be present in the bleb in sufficient amounts to trigger the excessive fibrotic responses.…”