Department of Physiology, School of Medicine, Kanazawa University, Kanazawa, Japan.
J Allergy Clin Immunol. 2013 Nov;132(5):1205-1214.e9. doi: 10.1016/j.jaci.2013.07.026. Epub 2013 Sep 8.
Sphingosine-1-phosphate receptor 2 (S1P(2)) 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 S1P(2) inhibits Akt, an activating kinase of eNOS.
We tested the hypothesis that endothelial S1P(2) might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis.
Mice deficient in S1P(2) and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms.
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.
S1P(2) diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P(2) agonists as novel therapeutic agents for anaphylaxis.
鞘氨醇-1-磷酸受体 2（S1P(2)）在血管内皮细胞（ECs）中表达。然而，S1P(2)在血管屏障完整性和过敏反应中的作用尚不清楚。内皮型一氧化氮合酶（eNOS）产生一氧化氮来介导血管渗漏，这会危及过敏反应患者的生命。我们最近观察到内皮 S1P(2)抑制 Akt，Akt 是 eNOS 的一种激活激酶。
我们检验了内皮 S1P(2)可能抑制 eNOS，从而对血管屏障破坏和过敏反应产生保护作用的假设。
S1P(2)和 eNOS 缺失的小鼠接受抗原挑战或血小板激活因子（PAF）注射。进行分析以检查血管通透性和潜在机制。
S1pr2 缺失增强了抗原挑战或 PAF 注射后的血管渗漏和死亡率。PAF 注射诱导 S1pr2 缺失小鼠的主动脉和肺中的 Akt 和 eNOS 激活，与野生型小鼠相比，这种激活增强。一致地，S1pr 缺失小鼠的主动脉中 PAF 诱导的环鸟苷单磷酸水平增加增强。遗传 Nos3 缺失或药理学 eNOS 阻断可保护 S1pr2 缺失小鼠免受抗原挑战和 PAF 注射后屏障破坏的加重。与野生型 ECs 相比，从 S1pr2 缺失的小鼠中分离出的 ECs 对鞘氨醇-1-磷酸或 PAF 的 Akt 和 eNOS 的刺激更大，产生更多的一氧化氮。此外，S1pr2 缺陷型 ECs 在受到 PAF 刺激时黏附连接的解体更严重，β-连环蛋白的 S-亚硝基化增加，而这种情况可通过药理学 eNOS 阻断来恢复。
S1P(2)减弱有害的强烈 eNOS 刺激，从而减轻血管屏障破坏，这表明 S1P(2)激动剂作为过敏反应的新型治疗药物具有潜在的用途。
