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The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function.

Ahmad F AlghanemJavier AbelloJoshua M MaurerAshutosh KumarChau My TaSusheel K GunasekarUrooj FatimaChen KangLitao XieOluwaseun AdeolaMegan RikerMacaulay Elliot-HudsonRachel A MinerathChad E GrueterRobert F MullinsAmber N StratmanRajan Sah
Published in: eLife (2021)
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.
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