Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice
Eric Camerer, … , Rajita Pappu, Shaun R. Coughlin
Eric Camerer, … , Rajita Pappu, Shaun R. Coughlin
Published June 15, 2009
Citation Information: J Clin Invest. 2009;119(7):1871-1879. https://doi.org/10.1172/JCI38575.
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Research Article Vascular biology

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 Gi-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.

Authors

Eric Camerer, Jean B. Regard, Ivo Cornelissen, Yoga Srinivasan, Daniel N. Duong, Daniel Palmer, Trung H. Pham, Jinny S. Wong, Rajita Pappu, Shaun R. Coughlin

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Figure 2

pS1Pless mice exhibit markedly increased sensitivity to systemic challenge with leak-inducing agents and are rescued by erythrocyte transfusion and acute S1pr1 agonism.

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pS1Pless mice exhibit markedly increased sensitivity to systemic challen...
(A) Survival after induction of PSA. (B) Hematocrit (HCT) determined 90 seconds after PSA induction. The change from baseline hematocrit, determined more than 7 days previously, is shown (mean ± SEM). (C) Survival after PAF injection (20 μg/kg i.v.). (D) Hematocrit measured 10 minutes after PAF injection. The change from baseline hematocrit, determined more than 7 days previously, is shown (mean ± SEM). (E and F) Mice were transfused with wild-type erythrocytes and studied 2 days later. (E) Survival of transfused mice after PAF injection (20 μg/kg i.v.). (F) Hematocrit determined 90 seconds after induction of PSA. The change from the hematocrit determined 2 hours previously is shown (mean ± SEM). Data were corrected for the drop in hematocrit caused by the blood draw at –2 hours. (G) Mice were injected with the S1pr1 agonist AUY954 (2 mg/kg i.v.) 2 minutes before PAF injection (20 μg/kg i.v.), and survival was followed. (H) Survival of pS1Pless mice and littermate controls after i.v. injection of histamine (200 mg/kg).