The Enigma of Sphingosine 1-Phosphate Synthesis

Abstract

See related article, pages 669–676 Sphingosine 1-phosphate (S1P) is well known as a key sphingolipid messenger molecule in the cardiovascular system, yet many fundamental features of its synthesis, transport, and action remain enigmatic. Indeed, the very name “sphingolipid” was coined to reflect the mysterious characteristics of this class of lipids. It is now well established (through the work of Timothy Hla and of many others subsequently) that S1P binds to and activates a family of G protein–coupled S1P receptors located in vascular endothelial cells, cardiac myocytes, blood platelets, and vascular smooth muscle cells (among other cell types) and elicits a broad range of physiological responses (reviewed elsewhere1). In vascular endothelial cells, S1P elicits such diverse responses as cell survival, proliferation, angiogenesis, cell migration, permeability, and endothelial NO synthase activation. The intracellular signaling pathways stimulated by S1P have been extensively characterized, yet the cellular origins of S1P and the pathways for its transport and action in cardiovascular tissues remain incompletely understood. The concentration of S1P in normal human plasma is within the range of several hundred nanomolar, and this amphipathic lipid is highly protein bound, mostly to HDL and albumin.2 Importantly, S1P receptors bind their ligand with an affinity in the nanomolar range; therefore, many important questions remain. What controls S1P binding to plasma proteins? Where does all this plasma S1P come from? Important clues to the latter question are provided in a recent report from the laboratory of Timothy Hla, published in this issue of Circulation Research 3 and reporting the novel and important discovery: the vascular endothelium is an important source of plasma S1P through the actions of sphingosine kinases (SphKs) in endothelial cells. For many years, conventional wisdom held that blood platelets represent the principal source for S1P in the plasma. Elegant studies by Igarashi …