The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
Ahmad F. Alghanem, Javier Abello, Joshua M Maurer, Ashutosh Kumar, Chau My Ta, Susheel K. Gunasekar, Urooj Fatima, Kang Chen, Litao Xie, Oluwaseun Adeola, Megan Riker, Macaulay Elliot-Hudson, Rachel A Minerath, Chad E. Grueter, Robert F. Mullins, Amber N. Stratman, Rajan Sah
Abstract
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.