Endothelial KCa3.1 and KCa2.3 Mediate S1P (Sphingosine-1-Phosphate)-Dependent Vasodilation and Blood Pressure Homeostasis
Endothelial KCa3.1 and KCa2.3 Mediate S1P (Sphingosine-1-Phosphate)-Dependent Vasodilation and Blood Pressure Homeostasis
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DOI：
10.1161/atvbaha.122.318820
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发表时间：
2023-05-01
影响因子：
8.7
通讯作者：
Xie, Wenjun
中科院分区：
文献类型：
--
作者：
Li, Jing-Jing;Zhao, Xin-Yi;Xie, Wenjun
背景：已有研究报道，1-磷酸鞘氨醇（S1P）具有血管舒张特性，但其潜在机制在很大程度上尚不明确。
方法：采用分离的小鼠肠系膜动脉和内皮细胞模型，来测定S1P诱导的血管舒张、细胞内钙浓度、膜电位以及钙激活钾通道（K(Ca)2.3和K(Ca)3.1，即内皮小电导和中电导钙激活钾通道）的变化。评估内皮S1P1型受体（S1PR1）缺失对血管舒张和血压的影响。
结果：急性S1P刺激的肠系膜动脉呈现剂量依赖性的血管舒张反应，而阻断内皮K(Ca)2.3或K(Ca)3.1通道可减弱这种反应。在培养的人脐静脉内皮细胞中，S1P激活K(Ca)2.3/K(Ca)3.1并使胞质Ca2+升高后，可立即刺激膜电位超极化。此外，慢性S1P刺激以剂量和时间依赖性方式增强人脐静脉内皮细胞中K(Ca)2.3和K(Ca)3.1的表达，而破坏S1PR1-Ca2+信号通路或下游Ca2+激活的钙调神经磷酸酶/活化T细胞核因子（NFAT）信号通路，均可消除这种增强作用。通过基于生物信息学的结合位点预测与染色质免疫沉淀试验相结合的方法，我们发现，在人脐静脉内皮细胞中，慢性激活S1P/S1PR1可促进NFATc2核转位并结合到K(Ca)2.3和K(Ca)3.1基因的启动子区域，从而上调这些通道的转录。内皮S1PR1缺失会降低肠系膜动脉中K(Ca)2.3和K(Ca)3.1的表达，并加剧血管紧张素II输注小鼠的高血压症状。
结论：本研究证实了K(Ca)2.3/K(Ca)3.1激活的内皮依赖性超极化在S1P介导的血管舒张和血压稳态调节中的机制作用。这一机制的阐明将有助于开发针对与高血压相关的心血管疾病的新疗法。
Background:S1P (sphingosine-1-phosphate) has been reported to possess vasodilatory properties, but the underlying pathways are largely unknown. Methods:Isolated mouse mesenteric artery and endothelial cell models were used to determine S1P-induced vasodilation, intracellular calcium, membrane potentials, and calcium-activated potassium channels (K(Ca)2.3 and K(Ca)3.1 [endothelial small- and intermediate-conductance calcium-activated potassium channels]). Effect of deletion of endothelial S1PR1 (type 1 S1P receptor) on vasodilation and blood pressure was evaluated. Results:Mesenteric arteries subjected to acute S1P stimulation displayed a dose-dependent vasodilation response, which was attenuated by blocking endothelial K(Ca)2.3 or K(Ca)3.1 channels. In cultured human umbilical vein endothelial cells, S1P stimulated immediate membrane potential hyperpolarization following activation of K(Ca)2.3/K(Ca)3.1 with elevated cytosolic Ca2+. Further, chronic S1P stimulation enhanced expression of K(Ca)2.3 and K(Ca)3.1 in human umbilical vein endothelial cells in dose- and time-dependent manners, which was abolished by disrupting either S1PR1-Ca2+ signaling or downstream Ca2+-activated calcineurin/NFAT (nuclear factor of activated T-cells) signaling. By combination of bioinformatics-based binding site prediction and chromatin immunoprecipitation assay, we revealed in human umbilical vein endothelial cells that chronic activation of S1P/S1PR1 promoted NFATc2 nuclear translocation and binding to promoter regions of K(Ca)2.3 and K(Ca)3.1 genes thus to upregulate transcription of these channels. Deletion of endothelial S1PR1 reduced expression of K(Ca)2.3 and K(Ca)3.1 in mesenteric arteries and exacerbated hypertension in mice with angiotensin II infusion. Conclusions:This study provides evidence for the mechanistic role of K(Ca)2.3/K(Ca)3.1-activated endothelium-dependent hyperpolarization in vasodilation and blood pressure homeostasis in response to S1P. This mechanistic demonstration would facilitate the development of new therapies for cardiovascular diseases associated with hypertension.