Endothelial K Ca 3.1 and K Ca 2.3 Mediate S1P (Sphingosine-1-Phosphate)–Dependent Vasodilation and Blood Pressure Homeostasis
| Autor: | Jing-Jing Li, Xin-Yi Zhao, Yan Wang, Rui Xu, Xiao-Hui Di, Yu Zhang, Hongyan Yang, Meng-Zhuan Han, Ru-Yue Bai, Lin Xie, Zheng-Da Pang, Xing Zhang, Jianbao Zhang, Xiao-Jun Du, Xiu-Ling Deng, Yi Zhang, Wenjun Xie |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 43:726-738 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.122.318820 |
| Popis: | 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 Ca 2+ . 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-Ca 2+ signaling or downstream Ca 2+ -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. |
| Databáze: | OpenAIRE |
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