Sphingosine-1-phosphate in the circulatory system: Cause and therapeutic target for vascular dysfunction?

Small arteries play an important role for blood pressure regulation and blood flow distribution to different organs. The diameter of these vessels is under the control of a number of factors such as blood pressure, flow, conducted signals from neighboring vessel segments, diverse metabolites produced from surrounding tissues, transmitters liberated from nerve endings, substances released from the endothelium, and a variety of vasoactive compounds washed ashore by the blood stream. Among these factors, increasing attention is now being given to bioactive sphingolipid metabolites, especially sphingosine-1-phosphate (S1P). A number of comprehensive reviews have summarized the current knowledge about S1P (for example, [1–4]). Briefly, S1P plays an important role in such diverse processes as cell migration, growth, shape change, survival, and apoptosis. This allows S1P to contribute to different pathological conditions, for example transplant rejection, sepsis, cancer, immunity, wound healing, and ischemia/reperfusion as well as restenosis, angiogenesis, vascular permeability, and vasospasm. S1P is derived from membrane phospholipids by enzymatic breakdown of sphingomyelin upon cell stimulation. The amount of available S1P is regulated by its synthesis by sphingosine kinase and its degradation by S1P phosphatase or S1P lyase. S1P is a normal component of blood plasma, present at concentrations between 0.2 and 0.5Amol/L. The concentration of S1P in serum is even higher because it is stored at high concentrations and is thought to be