The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

Abstract

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.

Based on Plasma Metabonomics and Network Pharmacology Exploring the Therapeutic Mechanism of Gynura procumbens on Type 2 Diabetes

“…In this study (Figure 6), AKT, iNS, eNOS, and MAPK were downregulated in the model group compared with the control group and significantly upregulated in the GP and MET groups compared with the model group. These results were in line with the data presented in previous reports (Alghanem et al, 2021;Cheng et al, 2021). As reported, the AGE-RAGE signaling pathway is closely associated with T2DM and inflammation (Syed et al, 2020).…”

Zinc pyrithione activates the volume-regulated anion channel through an antioxidant-sensitive mechanism

“…The identification of the LRRC8 gene family has revitalized the VRAC field, by confirming previously suspected roles and discovering new roles in adipocyte physiology, insulin signaling, vascular physiology, sperm development, drug uptake, immune responses to virus infection, and neurotransmitter release in the brain (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Many of these studies have highlighted the need for developing potent and specific pharmacological tools for probing the physiology and therapeutic potential of VRAC in human diseases.…”

From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

“…Hypotonic swelling has been shown to promote the release of NO and reactive nitrogen oxide species in various cells ( Kimura et al, 2000 ; Haussinger and Schliess, 2005 ; Takeda-Nakazawa et al, 2007 ; Kruczek et al, 2009 ; Gonano et al, 2014 ) and to augment LPS-triggered iNOS expression in RAW 264.7 macrophages ( Warskulat et al, 1998 ). Recently, it has been shown that in HUVECs, VRAC/SWELL1/LRRC8A mediates endothelial cell alignment via stretch-dependent Akt-eNOS signaling and formation of a signaling complex made up by Grb2, Cav-1, and eNOS ( Alghanem et al, 2021 ).…”

“…LRRC8A-E/SWELL1 proteins are essential components of the volume-regulated outwardly rectifying Cl – current (VRAC, VSOR, VSOAC, ICl swell , ICl vol ) elicited in most cells during cell swelling ( Qiu et al, 2014 ; Voss et al, 2014 ; Jentsch, 2016 ; Jentsch et al, 2016 ; Okada, 2020 ; Bertelli et al, 2021 ), and they are involved in a broad variety of cellular functions ( Chen et al, 2019 ). LRRC8A-E/SWELL1 also regulate the PI3K-Akt, Erk1/2, mTOR signaling cascade ( Kumar et al, 2020 ; Alghanem et al, 2021 ). Recently, Li et al (2020) demonstrated the expression of LRRC8 family members on lysosomal membranes and their ability to build functional lysosomal VRACs (Lyso-VRACs).…”