S1P Control of Endothelial Integrity

Abstract

Sphingosine 1-phosphate (S1P), a lipid mediator produced by sphingolipid metabolism, promotes endothelial cell spreading, vascular maturation/stabilization, and barrier function. S1P is present at high concentrations in the circulatory system, whereas in tissues its levels are low. This so-called vascular S1P gradient is essential for S1P to regulate much physiological and pathophysiological progress such as the modulation of vascular permeability. Cellular sources of S1P in blood has only recently begun to be identified. In this review, we summarize the current understanding of S1P in regulating vascular integrity. In particular, we discuss the recent discovery of the endothelium-protective functions of HDL-bound S1P which is chaperoned by apolipoprotein M.

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

“…As a barrier-enhancing GPCR, S1P 1 has been reported to regulate AJ by regulating VE-cadherin distribution in cultured ECs (10,41). Although our biochemical approach did not show any changes in VE-cadherin subcellular distribution in S1pr1 iECKO mice, alteration of the AJ structure or function may also be involved in the increased BBB leakage in these mice.…”

“…One possibility is that continuous activation of S1P 1 might be essential for cortical actin formation in brain ECs, which could directly facilitate proper maintenance of TJ protein complexes (35). Importantly, the S1P 1 /Rac pathway strongly induces cortical actin rearrangement by regulating actin-associated proteins, cortactin and myosin light chain kinase, in cultured ECs (10). Another possibility is that S1P 1 regulates phosphorylation of TJ proteins.…”

“…Furthermore, S1P and its prototypic receptor S1P 1 have been implicated in neurovascular diseases such as AD and ischemic stroke (8,9). S1P activation of EC S1P 1 is essential for vascular development and barrier function (10). S1P 1 regulates G i -dependent Rac activation, cytoskeletal reorganization, adherens junction (AJ) assembly, and focal adhesion formation, all of which are needed for enhancement of vascular barrier function (10).…”

“…S1P activation of EC S1P 1 is essential for vascular development and barrier function (10). S1P 1 regulates G i -dependent Rac activation, cytoskeletal reorganization, adherens junction (AJ) assembly, and focal adhesion formation, all of which are needed for enhancement of vascular barrier function (10). Indeed, genetic and pharmacological inhibition of S1P 1 increased vascular permeability in various organs such as lung, retina, and colon (11)(12)(13)(14).…”

Decreased plasma levels of the endothelial protective sphingosine-1-phosphate are associated with dengue-induced plasma leakage

“…Some of the pleiotropic actions of S1P are highly relevant for dengue infection, including the regulation of cell death and the modulation of immune cell trafficking, but especially the maintenance of the endothelial integrity. 4,5 The multiplicity of S1P-mediated actions can be explained by the fact that the sphingolipid on the one hand exhibits intracellular targets and on the other hand is able to stimulate G protein-coupled receptors (GPCR) after release into the extracellular environment. Until now five high-affinity receptors for S1P, designated S1P1eS1P5, have been discovered.…”