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 5

Effect of perturbing S1pr1 and Gi function on sensitivity to leak-inducing agents.

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Effect of perturbing S1pr1 and Gi function on sensitivity to leak-induci...
(A) Wild-type mice were injected with vehicle or AUY954 (2 mg/kg i.v.) either 2 minutes (solid orange line) or 4 hours (dashed orange line) prior to PAF injection (10 μg/kg i.v.), and survival was followed as a function of time. (B and C) Wild-type mice were injected with AUY954 or vehicle 4 hours before i.v. PAF challenge, and hematocrit (B) and lung weights (C) were determined 10 minutes after PAF. Note that prolonged but not brief exposure to AUY954 sensitized wild-type mice to PAF. Similar results were obtained in 4 separate experiments. Each point represents data for a separate mouse. The horizontal bars denote the mean. (D–F) Mice received vehicle or PTX (400 ng i.v.). Three days later, basal Evans blue extravasation into lung (D) and survival after PAF injection (E; 10 μg/kg i.v.) and histamine (F; 200 mg/kg i.v.) were assessed. In D, each point represents data for a separate mouse, and the horizontal bars denote the mean. (G) Poly(I:C)-induced Mx1-Cre–:ROSA26 Lox-STOP-Lox PTX S1, poly(I:C)-induced Mx1-Cre+:ROSA26 Lox-STOP-Lox PTX S1, or wild-type mice treated with i.v. PTX (400 ng) received PAF (10 μg/kg i.v.), and survival was followed. Note the failure of hematopoietic PTX expression to sensitize mice to PAF.