Sphingosine 1-Phosphate (S1P) Signaling and the Vasculature

Discovered more than 100 years ago, the bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P) was long believed to act as an intracellular second messenger, modulating many biological processes, including calcium mobilization, cell growth, differentiation, survival, motility, and cytoskeleton organization (1). The discovery that a protein whose expression was upregulated during endothelial cell differentiation and angiogenesis was a highaffinity receptor for S1P significantly accelerated research on this lipid (2, 3). This receptor, initially termed endothelial differentiation gene-1 (EDG-1) belongs to the family of G protein-coupled receptors with seven transmembrane domains, and its identification has led to the discovery of four other receptors for S1P. In keeping with nomenclature recommendations of the International Union of Pharmacology, S1P receptors are now referred to as S1Pn, with n = 1–5 (4). The fact that the first receptor identified for S1P is highly expressed in the endothelium, taken together with the finding that blood plasma contains large amounts of S1P (5, 6), suggests that S1P is likely to play a major role in vascular functions. Indeed, a survey of PubMed-indexed articles shows that nearly a third of the S1P-related literature deals with the vasculature. After a section on S1P synthesis and release in the vasculature, this review will therefore examine the functions of S1P receptors in endothelium and vascular smooth muscle cells (VSMCs), and their role in the regulation of angiogenesis, vascular permeability, inflammation, and tone. Because only three of the five S1P receptor subtypes (S1P1, S1P2, and S1P3), are expressed in vascular tissue, whereas expression of the S1P4 and S1P5 receptors are largely confined to cells of the immune and nervous systems, this chapter will mainly deal with the former three subtypes.