The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure and blood flow. The endothelial volume regulatory anion channel (VRAC) has been proposed to be mechano-sensitive 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-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.
RNA sequencing data has been deposited in GEO under accession number GSE166989. All other data available as source data files.
The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS- mTOR signaling and vascular functionNCBI Gene Expression Omnibus, GSE166989.
Article and author information
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106009)
- Rajan Sah
National Heart, Lung, and Blood Institute (5R00HL125683)
- Amber N Stratman
National Heart, Lung, and Blood Institute (R01 HL125436)
- Chad E Grueter
National Heart, Lung, and Blood Institute (R35 GM137976)
- Amber N Stratman
VA Merit Award (I01BX005072)
- Rajan Sah
King Abdullah International Medical Research Center (RA17-014-A)
- Ahmad F Alghanem
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to the approved institutional animal care and use committee (IACUC) protocols of Washington University in St. Louis (20180217) and the University of Iowa (1308148).
- Mark T Nelson, University of Vermont, United States
- Received: July 22, 2020
- Accepted: February 22, 2021
- Accepted Manuscript published: February 25, 2021 (version 1)
- Version of Record published: March 19, 2021 (version 2)
© 2021, Alghanem et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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