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The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
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The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
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Journal Article
The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
2021
Overview
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.
Publisher
eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
Subject
/ Animals
/ Calcium channels (voltage-gated)
/ Diabetes
/ Diabetes mellitus (non-insulin dependent)
/ Female
/ Male
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Nitric Oxide Synthase Type III - genetics
/ Nitric Oxide Synthase Type III - metabolism
/ Proteins
/ Proto-Oncogene Proteins c-akt - genetics
