Journal article
The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
eLife, Vol.10, p.1
02/25/2021
DOI: 10.7554/eLife.61313
PMID: 33629656
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.
Details
- Title: Subtitle
- The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
- Creators
- Ahmad F Alghanem - King Saud bin Abdulaziz University for Health SciencesJavier Abello - Washington University in St. LouisJoshua M Maurer - Washington University in St. LouisAshutosh Kumar - Washington University in St. LouisChau My Ta - Washington University in St. LouisSusheel K Gunasekar - Washington University in St. LouisUrooj Fatima - University of IowaChen Kang - Washington University in St. LouisLitao Xie - Washington University in St. LouisOluwaseun Adeola - University of IowaMegan Riker - University of IowaMacaulay Elliot-Hudson - University of IowaRachel A Minerath - University of IowaChad E Grueter - University of IowaRobert F Mullins - University of IowaAmber N Stratman - Washington University in St. LouisRajan Sah - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- eLife, Vol.10, p.1
- DOI
- 10.7554/eLife.61313
- PMID
- 33629656
- NLM abbreviation
- Elife
- ISSN
- 2050-084X
- eISSN
- 2050-084X
- Grant note
- DOI: 10.13039/100000062, name: National Institute of Diabetes and Digestive and Kidney Diseases, award: R01DK106009; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: 5R00HL125683; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: R01 HL125436; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: R35 GM137976; name: VA Merit Award, award: I01BX005072; DOI: 10.13039/100002002, name: Cancer Research Foundation, award: Young Investigator Award; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust; name: UIHC Center, award: I01B 005072
- Language
- English
- Date published
- 02/25/2021
- Academic Unit
- Cardiovascular Medicine; Craniofacial Anomalies Research Center; Neuroscience and Pharmacology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984182754102771
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