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

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• 作者：Hong Cui ; Yasuo Okamoto ; Kazuaki Yoshioka ; Wa Du ; Noriko Takuwa ; Wei Zhang ; Masahide Asano ; Toshishige Shibamoto ; Yoh Takuwa
• 关键词：Sphingosine-1-phosphate ; S1P2 ; vascular permeability ; anaphylaxis ; endothelial nitric oxide synthase ; nitric oxide ; nitrosylation ; 尾-catenin ; VE-cadherin ; adherens junction
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：November, 2013
• 年：2013
• 卷：132
• 期：5
• 页码：1205-1214.e9
• 全文大小：4068 K

文摘

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Background

Sphingosine-1-phosphate receptor 2 (S1P₂) is expressed in vascular endothelial cells (ECs). However, the role of S1P₂ 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 S1P₂ 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 尾-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.