Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice

Abstract

Maintenance of vascular integrity is critical for homeostasis, and temporally and spatially regulated vascular leak is a central feature of inflammation. Sphingosine-1-phosphate (S1P) can regulate endothelial barrier function, but the sources of the S1P that provide this activity in vivo and its importance in modulating different inflammatory responses are unknown. We report here that mutant mice engineered to selectively lack S1P in plasma displayed increased vascular leak and impaired survival after anaphylaxis, administration of platelet-activating factor (PAF) or histamine, and exposure to related inflammatory challenges. Increased leak was associated with increased interendothelial cell gaps in venules and was reversed by transfusion with wild-type erythrocytes (which restored plasma S1P levels) and by acute treatment with an agonist for the S1P receptor 1 (S1pr1). S1pr1 agonist did not protect wild-type mice from PAF-induced leak, consistent with plasma S1P levels being sufficient for S1pr1 activation in wild-type mice. However, an agonist for another endothelial cell G i -coupled receptor, Par2, did protect wild-type mice from PAF-induced vascular leak, and systemic treatment with pertussis toxin prevented rescue by Par2 agonist and sensitized wild-type mice to leak-inducing stimuli in a manner that resembled the loss of plasma S1P. Our results suggest that the blood communicates with blood vessels via plasma S1P to maintain vascular integrity and regulate vascular leak. This pathway prevents lethal responses to leak-inducing mediators in mouse models. IntroductionSphingosine-1-phosphate (S1P), a lipid phosphate produced in the course of sphingosine metabolism in all cell types (1), promotes endothelial cell spreading and barrier function in cell culture (2-5) and in vivo (6, 7). S1P can regulate cell behavior via 5 GPCRs, designated S1P receptor 1 (S1pr1) through S1pr5 (also known as S1P 1 -S1P 5 ) (1,4,8). Models of receptor-dependent roles for S1P in regulating endothelial barrier function have focused on S1P produced by the endothelial cells themselves, casting S1P as a downstream, autocrine/paracrine mediator of the barrier-protective effects of other agents such as activated protein C (9, 10) and angiopoietin (7). However, S1P is present at high concentrations in plasma (11), and the importance of this source of S1P in regulating vascular integrity has not been examined. In addition, GPCR-independent S1P signaling mechanisms and cell-autonomous metabolic effects of disrupting sphingosine conversion to S1P have been reported and may affect vascular integrity (1-5, 7, 12, 13). Central to understanding the physiological roles of S1P in regulating blood vessel function are identification of the sources of S1P that are important for barrier protection in vivo as well as determination of the importance of S1P from blood acting in trans on endothelial cells by receptor-dependent mechanisms ver-

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

“…8,14,38 A recent study using sphingosine kinases-null mice indicated that plasma S1P is required for vascular integrity. 16 Furthermore, administration of synthetic S1P 1 agonists, which powerfully induce downregulation of S1P 1 , but also that of S1P 1 antagonists induced pulmonary edema. 15,17,39 Therefore, S1P 1 seems to maintain vascular integrity in a tonic manner.…”

“…22,23 Different from S1P 2 , S1P 1 maintains not only constitutive barrier integrity but protects against barrier disruption caused by anaphylaxis and inflammation. 15,16,39 It is likely that S1P 1 protects the integrity of AJ through a mechanism different from eNOS-NO regulation. Thus, these observations together with the previous Cui 21 observations 27 suggest that receptor signaling mediated by G q/11 , G i and G 12/13 play distinct critical roles in triggering, preventing and limiting vascular leakage.…”

“…14,15 A subsequent study showed that plasma S1P is required to prevent vascular leakage in anaphylaxis after antigen challenge or injections of PAF and histamine. 16 Thus, the plasma S1P-endothelial S1P 1 axis plays Cui 7 a central role in maintaining vascular barrier integrity. 17 In contrast to S1P 1 , pharmacological blockade of S1P 2 was reported to reduce histamine-induced vascular leakage.…”

Sphingosine‐1‐phosphate signaling in physiology and diseases

“…The effectiveness of anti-S1P antibody is substantial and more than that obtained 16 with monoclonal anti-VEGF antibody. This anti-tumor effect is likely due to inhibition of both angiogenesis and tumor cell motility, survival and proliferation [44].…”

“…In addition, animal studies suggest that targeting the S1P signaling system is a promising strategy for inhibiting vascular hyperpermeability and modulating angiogenesis [13,15,16]. Here, we will overview the signaling mechanisms underlying S1P regulation of biological functions 5 and the roles of S1P in diseases.…”