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 S1P1-5, whereas only S1P1-3 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. LINKED ARTICLESThis article is one of a set of reviews submitted to BJP in connection with talks given at the September 2010 meeting of the International Society of Hypertension in Vancouver, Canada. To view the other articles in this collection visit http://dx.doi.org/ 10.1111/j. 1476-5381.2010.01167.x, http://dx.doi.org/10.1111/j.1476-5381.2011.01235.x and http://dx.doi.org/10.1111/ j.1476-5381.2011.01366.x Abbreviations ABC, ATP-binding cassette; ApoE, apolipoprotein E; Bcl-2, B-cell lymphoma gene 2; Bim, bisindolylmaleimide; CAD, coronary artery disease; Compound 5,thio]-2′-[4-(heptylthio)methyl]-2-hydroxyphenyl hydroxymethyl biphenyl-3-sulfonate; CYM5442, 2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino ethanol; EC, endothelial cell; ECM, extracellular matrix; EGF, endothelial growth factor; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; FTY720, 2-amino-2-(4-octylphenethyl) propane-1,3-diol; FTY720-P, 2-amino-2-(4-octylphenethyl) propane-1,3-diol phosphate; GPCR, G-protein coupled receptor; HDL, high-density lipoprotein; HUVEC, human umbilical vein endothelial cell; ICAM, inducible cell adhesion molecule; IL-8, interleukin 8; iNOS, inducible nitric oxide synthase; IP3, inositol-1,4,5-triphosphate; IRI, ischemia-reperfusion injury; JNK...

Sphingosine-1-Phosphate-Induced Airway Hyper-Reactivity in Rodents Is Mediated by the Sphingosine-1-Phosphate Type 3 Receptor

“…To obtain more information on the S1P receptors responsible for airway hyper-reactivity, we used AUY954, a selective S1P 1 receptor agonist (Pan et al, 2006;Schuchardt et al, 2011). It was important to establish that the intervention with AUY954 was truly a consequence of a high degree of selectivity for the S1P 1 receptor at the dose level used.…”

“…S1P exerts most of its actions by the activation of five G protein-coupled receptors designated S1P [1][2][3][4][5] (Alexander et al, 2011). S1P has been demonstrated to be an important regulator of vascular and gastric smooth muscle contraction (Zhou and Murthy, 2004;Schuchardt et al, 2011). At the level of airway smooth muscle, S1P has been demonstrated to stimulate contraction of human airway isolated smooth muscle cells (Rosenfeldt et al, 2003) and guinea pig isolated trachea (Kume et al, 2007).…”

Sphingosine but not Sphingosine-1-phosphate Stimulates Suicidal Erythrocyte Death

“…Ceramide stimulates the death of a wide variety of cells including neurons [67][68][69], Tlymphocytes [70], hepatocytes [71], epithelial cells [72] and erythrocytes [30,42,44,71,73]. Sphingolipids participate in cancer [64,[74][75][76][77][78][79], inflammatory disease [52,56,80,81] including lung inflammation and infection [82], cystic fibrosis [83], cardiovascular disease [84][85][86], Wilson´s disease [71], diabetes [87][88][89][90] and several neurological diseases [17,18,67,[91][92][93][94].…”

Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3

“…Of these, lysophospholipids, especially such as sphingosine-1-phosphate (S1P), activate eNOS in a G-protein coupled receptor (GPCR)-dependent manner [4e6]. S1P is involved in many physiological as well as in pathophysiological processes of arterial vascular diseases [7]. S1P acts as intracellular second messenger or activates GPCR-dependent S1P receptors on the cell surface.…”