Endothelial Functions of Sphingosine-1-phosphate

Abstract

The biologically active sphingolipid sphingosine-1-phosphate (S1P) plays key functions in the immune, inflammatory, and cardiovascular systems. In the vasculature, S1P and its receptors are involved in vessel morphogenesis and angiogenesis during embryonic development and in the adult organism both under normal and pathological conditions. Via its actions on endothelial and smooth muscle cells, S1P regulates arterial tone, vascular permeability, and tissue perfusion. Elevated local S1P levels during inflammation induce endothelial adhesion molecules, recruit inflammatory cells, and activate dendritic cells. At the same time, S1P activates a negative feedback loop that consecutively seals endothelial cell-cell contacts, decreases vascular leakage, and inhibits cytokine-induced leukocyte adhesion. Thus S1P determines not only the build-up, magnitude, and duration of an inflammatory reaction but also the pace of its resolution. This review focuses on the role S1P plays in endothelial function, its receptors and signalling pathways, and the role its major carrier high-density lipoproteins (HDL) play in its bioavailability and transport. We will also discuss the potential of interfering with S1P-S1P receptor interactions for the treatment of endothelial disorders and vascular pathologies.

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

“…The SphK activity, detected in endothelial cells upon LPS plus S1P treatment, suggests the involvement of the S1P-SphK axis, in addition to an interplay at the ERK, which has been reported to act upstream of SphK-1 (39). However, the contribution of TNF-ainduced endogenous S1P could not be ruled out because LPSinduced TNF-a expression and TNF-a-mediated activation of SphK-1-S1P signaling has been shown (2,11). The lack of TNF-a induction observed in cytokine arrays after 8 h of treatment with LPS plus S1P may suggest that the previous observations of LPS on TNF-a could be a secondary response that would not explain the short-term responses we report in this study with LPS plus S1P.…”

“…With regard to the pathophysiological role of S1P, even though it has been suggested that S1P could explain in part the atheroprotective effects of highdensity lipoproteins, both S1P-mediated anti-atherogenic and proatherogenic effects have been reported in the vascular system (8)(9)(10). In endothelial cells, S1P promotes the expression of adhesion molecules associated with angiogenesis and atherosclerosis processes and the expression of inflammation-related genes, although it also promotes anti-atherogenic effects (8)(9)(10)(11).…”

Structure of HDL: Particle Subclasses and Molecular Components

“…Among lysosphingolipids, S1P is particularly interesting as this bioactive lipid plays key roles in vascular biology (Lucke and Levkau 2010). More than 90 % of circulating sphingoid base phosphates are found in HDL and albumin-containing fractions (Table 3) (Kontush and Chapman 2012).…”

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

“…S1P carried by HDL is believed to regulate arterial tone, vascular permeability, and tissue perfusion. During inflammation it induces endothelial adhesion molecules and recruits inflammatory cells, and furthermore it activates a negative feedback loop that consecutively decreases vascular leakage by improving the endothelial barrier function and preventing cytokine-induced leukocyte adhesion (Garcia et al 2001;Lucke and Levkau 2010;Takeya et al 2003).…”