Pharmacological relevance and potential of sphingosine 1-phosphate in the vascular system

Abstract

Sphingosine-1-phosphate (S1P) was identified as a crucial molecule for regulating immune responses, inflammatory processes as well as influencing the cardiovascular system. S1P mediates differentiation, proliferation and migration during vascular development and homoeostasis. S1P is a naturally occurring lipid metabolite and is present in human blood in nanomolar concentrations. S1P is not only involved in physiological but also in pathophysiological processes. Therefore, this complex signalling system is potentially interesting for pharmacological intervention. Modulation of the system might influence inflammatory, angiogenic or vasoregulatory processes. S1P activates G-protein coupled receptors, namely S1P(1-5) , whereas only S1P(1-3) is present in vascular cells. S1P can also act as an intracellular signalling molecule. This review highlights the pharmacological potential of S1P signalling in the vascular system by giving an overview of S1P-mediated processes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). After a short summary of S1P metabolism and signalling pathways, the role of S1P in EC and VSMC proliferation and migration, the cause of relaxation and constriction of arterial blood vessels, the protective functions on endothelial apoptosis, as well as the regulatory function in leukocyte adhesion and inflammatory responses are summarized. This is followed by a detailed description of currently known pharmacological agonists and antagonists as new tools for mediating S1P signalling in the vasculature. The variety of effects influenced by S1P provides plenty of therapeutic targets currently under investigation for potential pharmacological intervention.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Figures

Figure 1

Ceramide is formed either de novo from serine, palmitoyl coA and fatty acid, or from breakdown of membrane-resident sphingomyelin. Ceramide is further converted to sphingosine, which could be phosphorylated to S1P. Degradation of S1P could be reversible by dephosphorylation or irreversible by S1P lyase. S1P, sphingosine-1-phosphate.

Figure 2

S1P is secreted by different blood cells, e.g. erythrocytes, thrombocytes and macrophages, or by endothelial cells (ECs). Once secreted, most of the S1P is uptaken by serum albumin or various serum lipoproteins. Intracellular-produced S1P in ECs or vascular smooth muscle cells could be transported across the membrane by ABC transporters. HDL, high-density lipoprotein; LDL, low-density lipoprotein; Sphk, sphingosine kinase; S1P, sphingosine-1-phosphate; VLDL, very low-density lipoprotein.

Figure 3

Diverse biological functions are regulated by S1P: (A) vascular relaxation and constriction, (B) endothelial integrity, (C) apoptosis, (D) monocyte adhesion/transmigration and inflammatory response, and (E) migration and proliferation. Arrows indicate activation and capped line inhibition. For more detailed information and references, see text. eNOS, endothelial nitric oxide synthase; ICAM, inducible cell adhesion molecule; IL-8, interleukin 8; MCP-1, monocyte chemoattractant protein-1; MMP-9, matrix metalloproteinase-9; PI3, phosphoinositide 3; PTEN, phosphatase and tensin homology; RANTES, regulated upon activation, normal t-cell expressed, and secreted; ROCK, Ras homolog gene family member-associated protein kinase; ROS, reactive oxygen species; Sphk, sphingosine kinase; VCAM, vascular cell adhesion molecule.