The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
| Autor: | Ahmad F. Alghanem, Ashutosh Kumar, Rajan Sah, Susheel K. Gunasekar, Joshua M Maurer, Litao Xie, Robert F. Mullins, Macaulay Elliot-Hudson, Chen Kang, Javier Abello, Oluwaseun Adeola, Chau My Ta, Rachel A Minerath, Megan J Riker, Chad E. Grueter, Urooj Fatima, Amber N. Stratman |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine hypertension Mouse Nitric Oxide Synthase Type III Endothelium QH301-705.5 Science Hydrostatic pressure General Biochemistry Genetics and Molecular Biology Umbilical vein Mice 03 medical and health sciences 0302 clinical medicine Enos medicine Animals Biology (General) General Immunology and Microbiology biology diabetes Chemistry General Neuroscience Membrane Proteins Cell Biology General Medicine mechanobiology biology.organism_classification Cell biology Nitric oxide synthase Endothelial stem cell 030104 developmental biology medicine.anatomical_structure ion channel biology.protein Medicine Female Mechanosensitive channels Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery Research Article Signal Transduction Blood vessel |
| Zdroj: | eLife, Vol 10 (2021) eLife |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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