Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice
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Background Sphingosine-1-phosphate receptor 2 (S1P2) is expressed in vascular endothelial cells (ECs). However, the role of S1P 2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective We tested the hypothesis that endothelial S1P 2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2-null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr-null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2-null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2-null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2-deficient ECs showed more severe disassembly of adherens junctions with augmented S-nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis. © 2013 American Academy of Allergy, Asthma & Immunology.
- Journal of Allergy and Clinical Immunology
Journal of Allergy and Clinical Immunology 132(5), 1205-1214, 2013-11-01