Li Jing-Jing, Zhao Xin-Yi, Wang Yan, Xu Rui, Di Xiao-Hui, Zhang Yu, Yang Hongyan, Han Meng-Zhuan, Bai Ru-Yue, Xie Lin, Pang Zheng-Da, Zhang Xing, Zhang Jianbao, Du Xiao-Jun, Deng Xiu-Ling, Zhang Yi, Xie Wenjun
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, China (J.-J.L., R.X., X.-H.D., L.X., J.Z., W.X.).
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Shaanxi, China (X.-Y.Z., Y.W., Y.Z., M.-Z.H., R.-Y.B., Z.-D.P., X.-J.D., X.-L.D., Y.Z.).
Arterioscler Thromb Vasc Biol. 2023 May;43(5):726-738. doi: 10.1161/ATVBAHA.122.318820. Epub 2023 Mar 23.
S1P (sphingosine-1-phosphate) has been reported to possess vasodilatory properties, but the underlying pathways are largely unknown.
Isolated mouse mesenteric artery and endothelial cell models were used to determine S1P-induced vasodilation, intracellular calcium, membrane potentials, and calcium-activated potassium channels (K2.3 and K3.1 [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.
Mesenteric arteries subjected to acute S1P stimulation displayed a dose-dependent vasodilation response, which was attenuated by blocking endothelial K2.3 or K3.1 channels. In cultured human umbilical vein endothelial cells, S1P stimulated immediate membrane potential hyperpolarization following activation of K2.3/K3.1 with elevated cytosolic Ca. Further, chronic S1P stimulation enhanced expression of K2.3 and K3.1 in human umbilical vein endothelial cells in dose- and time-dependent manners, which was abolished by disrupting either S1PR1-Ca signaling or downstream Ca-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 K2.3 and K3.1 genes thus to upregulate transcription of these channels. Deletion of endothelial S1PR1 reduced expression of K2.3 and K3.1 in mesenteric arteries and exacerbated hypertension in mice with angiotensin II infusion.
This study provides evidence for the mechanistic role of K2.3/K3.1-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.
据报道，1-磷酸鞘氨醇（S1P）具有血管舒张特性，但其潜在机制 largely 未知。
使用分离的小鼠肠系膜动脉和内皮细胞模型来确定 S1P 诱导的血管舒张、细胞内钙、膜电位以及钙激活钾通道（K2.3 和 K3.1[内皮小电导和中电导钙激活钾通道]）。评估内皮 S1PR1（1 型 S1P 受体）缺失对血管舒张和血压的影响。
急性 S1P 刺激的肠系膜动脉表现出剂量依赖性血管舒张反应，通过阻断内皮 K2.3 或 K3.1 通道可使其减弱。在培养的人脐静脉内皮细胞中，S1P 刺激后，随着胞质 Ca 升高激活 K2.3/K3.1，立即出现膜电位超极化。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 K2.3 和 K3.1 的表达，通过破坏 S1PR1-Ca 信号或下游 Ca 激活的钙调神经磷酸酶/NFAT（活化 T 细胞核因子）信号可消除这种增强。通过基于生物信息学的结合位点预测和染色质免疫沉淀分析相结合，我们在人脐静脉内皮细胞中发现，S1P/S1PR1 的慢性激活促进 NFATc2 核转位并与 K2.3 和 K3.1 基因的启动子区域结合，从而上调这些通道的转录。内皮 S1PR1 的缺失降低了肠系膜动脉中 K2.3 和 K3.1 的表达，并加重了输注血管紧张素 II 的小鼠的高血压。
本研究为 K2.3/K3.1 激活的内皮依赖性超极化在响应 S1P 时的血管舒张和血压稳态中的机制作用提供了证据。这种机制证明将有助于开发与高血压相关的心血管疾病的新疗法。
