Sphingosine-1-phosphate in the regulation of vascular tone: a finely tuned integration system of S1P sources, receptors, and vascular responsiveness.

Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid that plays an important role in the physiology of the cardiovascular, nervous and immune systems.1 Red blood cells are the major source of plasma S1P, where it mainly associates with High-density lipoproteins (HDL). There is a steep concentration gradient of S1P between plasma and the interstitial compartment, with S1P being present in the low micromolar range in plasma and at least 1 order of magnitude lower in the interstitial fluid. S1P exerts numerous effects on the vascular cells regulating arterial tone— the smooth muscle cell and the endothelial cell —via a set of 5 cognate G protein–coupled receptors (S1P1 to 5) expressed differentially in the different cell types.2 In addition, S1P has negative effects on cardiac rate, contractility, and output. All of this makes S1P a candidate for a bona fide modulator of vascular tone. Direct vasoactive effects of S1P have been studied both in isolated vessel strips ex vivo and different vascular territories in vivo.2 The consensus from all these studies is that S1P induces vasoconstriction in resistance vessels such as mesenteric, cerebral, and coronary arteries but has little or no effect on conduit vessels such as aorta, carotid, and femoral arteries. This implies S1P as a player in the control of blood flow in the periphery. However, these studies have been all performed by using exogenously added S1P, making it difficult to draw conclusions on the role of endogenous S1P sources in the homoeostatic regulation of resistance artery tone. In a previous study, this has been addressed by Bolz et al by overexpressing sphingosine kinase (Sphk)1 in hamster resistance arteries, showing that endogenously produced S1P participates in the regulation of basal tone, as well as that of the myogenic response,3 the unique intrinsic ability of resistance arteries to react through vasoconstriction to elevation in transmural pressure caused by raises in systemic blood pressure to keep a constant blood flow to the supplied tissues. In this issue of Circulation Research, Peter et al4 expand their previous studies by showing that a balance between S1P-generating and -degrading enzymes inside the vascular wall is responsible for the regulation of basal and myogenic resistance artery tone in the hamster gracilis muscle resistance artery. Overexpression of the S1P degrading enzyme S1P-phosphohydrolase (SPP)1 reduced basal tone and myogenic vasoconstriction and antagonized the increase in myogenic tone induced by overexpression of S1P-generating Sphk1. Moreover, SPP1 was also able to counteract the vasoconstriction induced by exogenously added S1P, suggesting that it was able to efficiently degrade extracellular S1P. As SPP1 is known to be localized in the endoplasmic reticulum (ER) rather than the plasma membrane Peter et al hypothesized that it must have sufficient access to the pool of extracellular S1P for degradation if it were to restrain its vasoconstrictive action. Indeed, the study shows that such access was granted by cystic fibrosis transmembrane conductance regulator (CFTR) (also known as ATP-binding cassette subfamily C member 7 [ABCC7]), the only known outside-in transporter for S1P that had also been proven capable of preventing interaction of S1P with its cell surface receptors by diverting sufficient quantities of extracellular S1P to the inside of the cell (Figure 1).5 Using an inhibitor of CFTR [CFTR(inh)-172], Peter et al could reverse the reduced resting tone and myogenic vasoconstriction caused by SPP1 overexpression. Consequently, a conclusive model of resistance artery tone regulation by endogenous, smooth muscle cell–derived S1P emerges, in which S1P production by Sphk1 and its degradation by SPP1 after CFTR-mediated import together determine the amount of biologically active S1P concentration presented at the S1P receptor level for vasoconstriction (Figure). Much work has been done to identify which S1P receptors are responsible for its vasoconstrictive effect. S1P1–3 are expressed in smooth muscle cells. However, smooth muscle cells from different arterial beds appear to have different relative expression levels of the 3 receptors, which has been proposed as an explanation for the different potency of S1P-mediated vasoconstriction between, eg, aorta and cerebral arteries.6 The most informative studies with respect to which S1P receptor(s) influence the physiological regulation of vascular tone and blood pressure/blood flow relationship have emerged from studies using S1P2and S1P3-deficient mice. In S1P3-deficient mice, S1P did not affect basilar artery vascular tone, while inducing regular vasoconstriction in wild-type and S1P2-deficient mice, suggesting that it constricts cerebral arteries via S1P3. In contrast, S1P2-deficient mice were shown to exhibit normal blood pressure but clearly decreased resting vascular tone and contractile responsiveness to -adrenergic stimulation, resulting in elevation of regional blood flow and a decrease in vascular resistance.8 Thus S1P2 appears to have a crucial role in the regulation of The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Institute of Pathophysiology, University Hospital Essen, Germany. Correspondence to Bodo Levkau, Institute of Pathophysiology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail [email protected] (Circ Res. 2008;103:231-233.) © 2008 American Heart Association, Inc.