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 3

pS1Pless mice exhibit increased fluid accumulation in lung during PSA.

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pS1Pless mice exhibit increased fluid accumulation in lung during PSA. (...
(A and B) Lung wet, dry, and wet/dry weights in pS1Pless mice (red circles) and controls (black circles) 90 seconds after DNP-albumin challenge in PSA model without (A) and 2 days after (B) transfusion with wild-type erythrocytes. Note that without transfusion, lung wet/dry weights were increased in pS1Pless mice relative to control mice after PSA, and this difference was absent after transfusion. P values were determined using the Student’s t test. Each point represents data for one mouse. The horizontal bars denote the mean. (C) Histology of lungs fixed 8 minutes after PSA (H&E stain) showing peribronchial fluid accumulation (arrows), likely representing extravasated plasma in lymphatics. This feature was much more prominent in pS1Pless mice. Alveolar wall thickening, suggesting interstitial fluid accumulation, red blood cells in airspace (arrowhead), and epithelial blebbing (asterisk), were also more prominent in pS1Pless mice compared with controls after PAF injection. Scale bars: 500 μm.