Phospholipase A2 in Vascular Disease Prostaglandin H Synthase and Vascular Function Cytochrome P450 Enzymes in Vascular Homeostasis Sphingolipid Mediators in Cardiovascular Cell Biology and Pathology Point-Counterpoint of Sphingosine 1-Phosphate Metabolism

Sphingosine 1-phosphate (S1P), an evolutionarily conserved bioactive lipid mediator, is now recognized as a potent modulator of cell regulation. In vertebrates, S1P interacts with cell surface G protein–coupled receptors of the EDG family and induces profound effects in a variety of organ systems. Indeed, an S1P receptor agonist is undergoing clinical trials to combat immune-mediated transplant rejection. Recent information on S1P receptor biology suggests potential utility in the control of cardiovascular processes, including angiogenesis, vascular permeability, arteriogenesis, and vasospasm. However, studies from diverse invertebrates, such as yeast, Dictyostelium, Drosophila, and Caenorhabditis elegans have shown that S1P is involved in important regulatory functions in the apparent absence of EDG S1P receptor homologues. Metabolic pathways of S1P synthesis, degradation, and release have recently been described at the molecular level. Genetic and biochemical studies of these enzymes have illuminated the importance of S1P signaling systems both inside and outside of cells. The revelation of receptor-dependent pathways, as well as novel metabolic/intracellular pathways has provided new biological insights and may ultimately pave the way for the development of novel therapeutic approaches for cardiovascular diseases. (Circ Res. 2004;94:724-734.)