Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.61313
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [R01DK106009]
- National Heart, Lung, and Blood Institute [5R00HL125683, R01 HL125436, R35 GM137976]
- VA Merit Award [I01BX005072]
- Cancer Research Foundation Young Investigator Award
- Roy J. Carver Charitable Trust
- UIHC Center [I01B 005072]
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The LRRC8A-dependent volume-regulated anion channel (VRAC) is crucial for regulating vascular function and is particularly important in the context of type 2 diabetes (T2D). LRRC8A modulates endothelial cell function in the vascular system by regulating signaling pathways such as AKT-eNOS.
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.
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