D Vara
Direct activation of NADPH oxidase 2 by 2-deoxyribose-1-phosphate triggers nuclear factor kappa B-dependent angiogenesis.
Vara, D; Watt, J M; Fortunato, T M; Mellor, H; Burgess, M; Wicks, K; Mace, K; Reeksting, S; Lubben, A T; Wheeler-Jones, C P D; Pula, G
Authors
J M Watt
T M Fortunato
H Mellor
M Burgess
K Wicks
K Mace
S Reeksting
A T Lubben
C P D Wheeler-Jones
G Pula
Abstract
AbstractAims: Deoxyribose-1-phosphate (dRP) is a proangiogenic paracrine stimulus released by cancer cells, platelets, and macrophages and acting on endothelial cells. The objective of this study was to clarify how dRP stimulates angiogenic responses in human endothelial cells.Results: Live cell imaging, electron paramagnetic resonance, pull-down of dRP-interacting proteins, followed by immunoblotting, gene silencing of different NADPH oxidases (NOXs), and their regulatory cosubunits by small interfering RNA (siRNA) transfection, and experiments with inhibitors of the sugar transporter glucose transporter 1 (GLUT1) were utilized to demonstrate that dRP acts intracellularly by directly activating the endothelial NOX2 complex, but not NOX4. Increased reactive oxygen species generation in response to NOX2 activity leads to redox-dependent activation of the transcription factor nuclear factor kappa B (NF-κB), which, in turn, induces vascular endothelial growth factor receptor 2 (VEGFR2) upregulation. Using endothelial tube formation assays, gene silencing by siRNA, and antibody-based receptor inhibition, we demonstrate that the activation of NF-κB and VEGFR2 is necessary for the angiogenic responses elicited by dRP. The upregulation of VEGFR2 and NOX2-dependent stimulation of angiogenesis by dRP were confirmed in excisional wound and Matrigel plug vascularization assays in vivo using NOX2−/− mice.Innovation: For the first time, we demonstrate that dRP acts intracellularly and stimulates superoxide anion generation by direct binding and activation of the NOX2 enzymatic complex.Conclusions: This study describes a novel molecular mechanism underlying the proangiogenic activity of dRP, which involves the sequential activation of NOX2 and NF-κB and upregulation of VEGFR2. Antioxid. Redox Signal. 28, 110–130.
Citation
Vara, D., Watt, J. M., Fortunato, T. M., Mellor, H., Burgess, M., Wicks, K., …Pula, G. (2017). Direct activation of NADPH oxidase 2 by 2-deoxyribose-1-phosphate triggers nuclear factor kappa B-dependent angiogenesis. https://doi.org/10.1089/ars.2016.6869
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 19, 2016 |
Publication Date | Aug 10, 2017 |
Deposit Date | Aug 15, 2017 |
Publicly Available Date | Aug 15, 2017 |
Journal | Antioxidants & Redox Signaling |
Peer Reviewed | Peer Reviewed |
Volume | 28 |
Issue | 2 |
Pages | 110-130 |
DOI | https://doi.org/10.1089/ars.2016.6869 |
Public URL | https://rvc-repository.worktribe.com/output/1390896 |
Files
10915.pdf
(2.9 Mb)
PDF
10915.pdf
(8.8 Mb)
PDF
You might also like
Equine endothelial cells show pro-angiogenic behaviours in response to FGF2 but not VEGF-A.
(2024)
Journal Article
The immunomodulatory effects of statins on macrophages Author information
(2022)
Journal Article
Downloadable Citations
About RVC Repository
Administrator e-mail: publicationsrepos@rvc.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search