The endothelium responds to chemical and mechanical factors in regulating vascular tone, angiogenesis, blood pressure and blood flow. The endothelial volume regulatory anion channel (VRAC) has been proposed to be mechano-sensitive, to activate in response to fluid flow/hydrostatic pressure and putatively regulate vascular reactivity and angiogenesis. Here, we show that the Leucine Rich Repeat Containing Protein 8a, LRRC8a (SWELL1) functionally encodes VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial SWELL1 expression positively regulates AKT-eNOS signaling while negatively regulating mTOR signaling, via a SWELL1-GRB2-Cav1-eNOS signaling complex. Endothelium-restricted SWELL1 KO mice exhibit enhanced tube formation from ex-vivo aortic ring explants in matrigel angiogenesis assays, develop hypertension in response to chronic angiotensin II infusion and have impaired retinal blood flow with blood vessel narrowing in the setting of Type 2 diabetes (T2D). These data demonstrate that SWELL1 antithetically regulates AKT-eNOS and mTOR signaling in endothelium and is required for maintaining vascular function.

中文翻译：

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SWELL1-LRRC8复合物调节内皮AKT-eNOS-mTOR信号和血管功能

内皮对调节血管紧张，血管生成，血压和血流的化学和机械因素起反应。已经提出内皮体积调节阴离子通道（VRAC）是机械敏感的，以响应于流体流量/静水压力而活化并推测调节血管反应性和血管生成。在这里，我们显示，富含亮氨酸的重复序列包含蛋白8a，LRRC8a（SWELL1）在人脐静脉内皮细胞（HUVEC）中功能性编码VRAC。内皮SWELL1表达通过SWELL1-GRB2-Cav1-eNOS信号复合物正调控AKT-eNOS信号，而负调控mTOR信号。在基质胶血管生成测定中，内皮受限的SWELL1 KO小鼠的离体主动脉环外植体显示出增强的管形成，在慢性2型糖尿病（T2D）的情况下，由于长期接受血管紧张素II输注而发展为高血压，并且视网膜血流受损且血管变窄。这些数据表明，SWELL1在内皮中可调节AKT-eNOS和mTOR信号传导，是维持血管功能所必需的。