Abstract
The Swell1-LRRC8 Complex Regulates Endothelial PI3K-AKT2-GRB2-eNOS Signaling and Vascular Function
Biophysical journal, Vol.116(3), pp.376a-376a
02/15/2019
DOI: 10.1016/j.bpj.2018.11.2043
Abstract
The endothelium responds to various 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, to activate in response to fluid flow/hydrostatic pressure and putatively regulate vascular reactivity. Here we show that the Leucine Rich Repeat Containing Protein 8a, LRRC8a (SWELL1) functionally encodes VRAC in human umbilical vein endothelial cells (HUVECs). shRNA-mediated SWELL1 knock-down impairs insulin and stretch-induced PI3K-AKT2-eNOS signaling. Endothelial SWELL1 interacts with GRB2-Cav1-eNOS. Both GRB2 knock-down and SWELL1 overexpression augment insulin-induced PI3K-AKT2-eNOS signaling in HUVECs. Consistent with SWELL1-dependent PI3K-AKT2-eNOS signaling in endothelium, endothelial-restricted SWELL1 KO mice (eSWELL1 KO) are mildly hypertensive, and exhibit mildly impaired retinal blood flow with both diffuse and focal blood vessel narrowing compared to littermate controls when raised on a regular chow diet. This reduction in retinal blood flow, reduced blood vessel size and extent of focal vessel narrowing is further exacerbated in the setting of Type 2 diabetes (T2D) when eSWELL1 KO mice are raised on a high-fat, high-sucrose diet. These data demonstrate that SWELL1 regulates PI3K-AKT2-GRB2-eNOS signaling in endothelium and is required for maintaining vascular function, particularly in the setting of T2D.
Details
- Title: Subtitle
- The Swell1-LRRC8 Complex Regulates Endothelial PI3K-AKT2-GRB2-eNOS Signaling and Vascular Function
- Creators
- Ahmad F Alghanem - Washington University in St. Louis School of MedicineChau Ta - Washington University in St. Louis School of MedicineOluwaseun Adeola - University of IowaSusheel K Gunasekar - Washington University in St. Louis School of MedicineUrooj Fatima - Howard UniversityElliot-Hudson Elliot-Hudson - University of IowaYanhui Zhang - Xiamen UniversityMegan Riker - University of IowaRobert F Mullins - University of IowaLitao Xie - Washington University in St. Louis School of MedicineRajan Sah - Washington University in St. Louis School of Medicine
- Resource Type
- Abstract
- Publication Details
- Biophysical journal, Vol.116(3), pp.376a-376a
- DOI
- 10.1016/j.bpj.2018.11.2043
- ISSN
- 0006-3495
- eISSN
- 1542-0086
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 02/15/2019
- Academic Unit
- Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984182755102771
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