Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system

The plasma lysophospholipid mediator sphingosine-l-phosphate (SIP) is produced exclusively by sphingosine kinase (SPHI) 1 and SPHK2 in vivo, and plays diverse biological and pathophysiological roles by acting largely through three members of the G protein-coupled S1P receptors. S1P(1), S1P(2) and S1P(3) S1P(1) expressed on endothelial cells mediates embryonic vascular Maturation and maintains vascular integrity by contributing to eNOS activation, inhibiting Vascular permeability and inducing endothelial cell chemotaxis Via Gi-coupled mechanisms. By contrast, S1P(2), is expressed in high levels oil vascular smooth muscle cells (VSMCs) and certain types of tumor cells, inhibiting Rac and cell migration via a G(12/13)-and Rho-dependent mechanism.In rat neointimal VSMCs, S1P, is upregulated to mediate local production of platelet-derived growth factor, which is a key player in vascular remodeling.S1P(3) expressed oil endothelial cells also mediates chemotaxis toward S1P and vasorelaxation via NO production in certain vascular bed, playing protective roles for vascular integrity. S1P(3) expressed on VSMCs and cardiac sinoatrial node cells mediates vasopressor and negative chronotropic effect, respectively. In addition, S1P(3) together with S1P(2) and SPHK1, is suggested to play a protective role against acute myocardial ischemia. However, our recent work indicates that overexpressed SPHK1 is involved in cardiomyocyte degeneration and fibrosis in vivo, in part through SIP activation of the S1P(3) signaling. We also demonstrated that exogenously administered S1P accelerates neovascularization and blood flow recovery in ischemic limbs, suggesting its usefulness for angiogenic therapy. These results provide evidence for S1P receptor subtype-specific pharmacological intervention as a novel therapeutic approach to cardiovascular diseases and cancer. (c) 2008 Elsevier B.V. All rights reserved.