PT - JOURNAL ARTICLE AU - Ahmad F. Alghanem AU - Chau Ta AU - Joshua M. Maurer AU - Susheel K. Gunasekar AU - Ashutosh Kumar AU - Urooj Fatima AU - Chen Kang AU - Litao Xie AU - Oluwaseun Adeola AU - Javier Abello AU - Megan Riker AU - Macaulay Elliot-Hudson AU - Rachel A. Minerath AU - Amber Stratman AU - Chad E. Grueter AU - Robert F. Mullins AU - Rajan Sah TI - The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS-mTOR signaling and vascular function AID - 10.1101/2020.08.04.236182 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.08.04.236182 4099 - http://biorxiv.org/content/early/2020/08/04/2020.08.04.236182.short 4100 - http://biorxiv.org/content/early/2020/08/04/2020.08.04.236182.full AB - The endothelium responds to a multitude of 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 (SWELL1) expression positively regulates AKT-eNOS signaling while negatively regulating mTOR signaling, via a SWELL1-GRB2-Cav1-eNOS signaling complex. Endothelium-restricted SWELL1 KO (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 both diffuse and focal 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, particularly in the setting of T2D.