TY - JOUR TI - The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function AU - Alghanem, Ahmad F AU - Abello, Javier AU - Maurer, Joshua M AU - Kumar, Ashutosh AU - Ta, Chau My AU - Gunasekar, Susheel K AU - Fatima, Urooj AU - Kang, Chen AU - Xie, Litao AU - Adeola, Oluwaseun AU - Riker, Megan AU - Elliot-Hudson, Macaulay AU - Minerath, Rachel A AU - Grueter, Chad E AU - Mullins, Robert F AU - Stratman, Amber N AU - Sah, Rajan A2 - Nelson, Mark T A2 - Swartz, Kenton J A2 - Nelson, Mark T A2 - Sukumar, Piruthivi VL - 10 PY - 2021 DA - 2021/02/25 SP - e61313 C1 - eLife 2021;10:e61313 DO - 10.7554/eLife.61313 UR - https://doi.org/10.7554/eLife.61313 AB - 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. KW - ion channel KW - mechanobiology KW - hypertension KW - diabetes JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -