The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function.
The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function.
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作者：
Alghanem AF;Abello J;Maurer JM;Kumar A;Ta CM;Gunasekar SK;Fatima U;Kang C;Xie L;Adeola O;Riker M;Elliot-Hudson M;Minerath RA;Grueter CE;Mullins RF;Stratman AN;Sah R
内皮细胞对许多化学和机械因素作出反应，调节血管张力、血压和血流。内皮容量调节阴离子通道（VRAC）被认为是机械敏感的，从而感知流体流量和静水压力来调节血管功能。在这里，我们表明，富含亮氨酸的重复蛋白8a，LRRC 8A（SWELL 1），是需要VRAC在人脐静脉内皮细胞（HUVECs）。内皮LRRC 8A在基础、拉伸和剪切流刺激下调节AKT-内皮一氧化氮合酶（eNOS）信号传导，形成GRB 2-Cav 1-eNOS信号传导复合物，并且是内皮细胞对准层流剪切流所需的。内皮限制性Lrrc 8a KO小鼠响应于慢性血管紧张素-II输注而发展高血压，并且在2型糖尿病（T2 D）的情况下表现出视网膜血流受损，伴有弥漫性和局灶性血管狭窄。这些数据表明，LRRC 8A调节内皮中的AKT-eNOS，并且是维持血管功能所需的，特别是在T2 D的情况下。
The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure, and blood flow. The endothelial volume-regulated anion channel (VRAC) has been proposed to be mechanosensitive and thereby sense fluid flow and hydrostatic pressure to regulate vascular function. Here, we show that the leucine-rich repeat-containing protein 8a, LRRC8A (SWELL1), is required for VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial LRRC8A regulates AKT-endothelial nitric oxide synthase (eNOS) signaling under basal, stretch, and shear-flow stimulation, forms a GRB2-Cav1-eNOS signaling complex, and is required for endothelial cell alignment to laminar shear flow. Endothelium-restricted Lrrc8a KO mice develop hypertension in response to chronic angiotensin-II infusion and exhibit impaired retinal blood flow with both diffuse and focal blood vessel narrowing in the setting of type 2 diabetes (T2D). These data demonstrate that LRRC8A regulates AKT-eNOS in endothelium and is required for maintaining vascular function, particularly in the setting of T2D.