S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure.
S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure.
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DOI：
10.1161/hypertensionaha.117.09088
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发表时间：
2017-08
期刊：
影响因子：
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通讯作者：
Di Lorenzo A
中科院分区：
文献类型：
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作者：
Cantalupo A;Gargiulo A;Dautaj E;Liu C;Zhang Y;Hla T;Di Lorenzo A
一氧化氮是调节血压的主要内皮源性血管活性因子之一，生物活性脂质介质 S1P 是通过 G 蛋白偶联受体有效激活内皮一氧化氮合酶的因子。内皮源性 S1P 和 S1P 受体的自分泌/旁分泌激活在维持血管功能和血压稳态方面发挥着重要作用。此外，FTY720 与 FDA 最近批准用于治疗自身免疫性疾病的 5 个 S1PR 中的 4 个结合，可诱导动物和人类心率适度且短暂地降低，表明针对鞘脂信号传导的药物会影响体内心血管功能。然而，特定 S1P 受体在血压稳态中的作用仍不清楚。本研究的目的是确定关键血管 S1P 受体（即 S1PR1 和 S1PR3）在生理和高血压条件下血压调节中的作用。内皮 S1PR1 的特异性缺失会减少基础和刺激的内皮源性 NO，并将血压重置至高于正常值。有趣的是，我们发现 S1PR1 信号在流介导的机械转导中具有新颖且重要的作用。 FTY720（芬戈莫德）作为 S1PR1 的功能性拮抗剂，显着降低内皮 S1PR1，增加对照小鼠的血压，并加剧 Ang-II 小鼠模型的高血压，强调了 S1PR1 信号传导的抗高血压功能。我们的研究确定S1P-S1PR1-NO信号传导是体内血管舒张、血流和血压稳态的新调节途径，为高血压的治疗提供了新的治疗靶点。
Nitric oxide is one of the major endothelial-derived vasoactive factors that regulate blood pressure and the bioactive lipid mediator S1P is a potent activator of endothelial nitric oxide synthase through G-protein coupled receptors. Endothelial-derived S1P and the autocrine/paracrine activation of S1P receptors play an important role in preserving vascular functions and blood pressure homeostasis. Furthermore, FTY720, binding to four out of five S1PRs recently approved by the FDA to treat autoimmune conditions, induces a modest and transient decrease in heart rate in both animals and humans, suggesting that drugs targeting sphingolipid signaling affect cardiovascular functions in vivo. However, the role of specific S1P receptors in BP homeostasis remains unknown. The aim of this study is to determine the role of the key vascular S1P receptors, namely, S1PR1 and S1PR3 in BP regulation in physiological and hypertensive conditions. The specific loss of endothelial S1PR1 decreases basal and stimulated endothelial-derived NO, and re-sets blood pressure to a higher-than-normal value. Interestingly, we identified a novel and important role for S1PR1 signaling in flow-mediated mechanotransduction. FTY720 (fingolimod), acting as functional antagonist of S1PR1, markedly decreases endothelial S1PR1, increases blood pressure in control mice and exacerbates hypertension in Ang-II mouse model, underlining the anti-hypertensive functions of S1PR1 signaling. Our study identifies S1P-S1PR1-NO signaling as a new regulatory pathway in vivo of vascular relaxation to flow and blood pressure homeostasis, providing a novel therapeutic target for the treatment of hypertension.