The plasma lysophospholipid mediator sphingosine-1-phosphate (S1P) is produced exclusively by sphingosine kinase (SPHK) 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 on 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 1 is upregulated to mediate local production of platelet-derived growth factor, which is a key player in vascular remodeling. S1P 3 expressed on 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 S1P 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.
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Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system
Takuwa, Yoh; Okamoto, Yasuo; Yoshioka, Kazuaki; Takuwa, Noriko
Follow Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
, Volume 1781 (9)
Elsevier – Sep 1, 2008
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