dc.contributor.author | Vara, Dina | |
dc.contributor.author | Watt, Joanna M | |
dc.contributor.author | Fortunato, Tiago M | |
dc.contributor.author | Mellor, Harry | |
dc.contributor.author | Burgess, Matthew | |
dc.contributor.author | Wicks, Kate | |
dc.contributor.author | Mace, Kimberley | |
dc.contributor.author | Shaun, Reeksting | |
dc.contributor.author | Anneke, Lubben | |
dc.contributor.author | Wheeler-Jones, Caroline PD | |
dc.contributor.author | Pula, Giordano | |
dc.date.accessioned | 2017-08-07T11:37:59Z | |
dc.date.issued | 2017-09-18 | |
dc.description.abstract | Aims: Deoxyribose-1-phosphate (dRP) is a pro-angiogenic 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 (EPR), pull-down of dRPinteracting
proteins followed by immunoblotting, gene silencing of different NOXs and their
regulatory co-subunits by siRNA transfection, and experiments with inhibitors of the sugar
transporter GLUT1 were utilized to demonstrate that dRP acts intracellularly by directly
activating the endothelial NADPH oxidase 2 (NOX2) complex, but not NOX4. Increased
reactive oxygen species (ROS) generation in response to NOX2 activity leads to redoxdependent
activation of the transcription factor nuclear factor kappa B (NF-κB), which, in turn,
induces VEGF 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 the NOX2-dependent stimulation of angiogenesis by dRP was
confirmed in excisional wound and matrigel plug vascularisation 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 pro-angiogenic
activity of dRP, which involves the sequential activation of NOX2 and NF-κB and the
upregulation of VEGFR2 | en_GB |
dc.description.sponsorship | This work was sponsored by the Biotechnology and Biological Sciences Research Council
(BB/J002690/1), the Medical Research Council (MRC/CIC/2015) and the British Heart
Foundation (PG/15/40/31522) | en_GB |
dc.identifier.citation | Published online 18 September 2017 | en_GB |
dc.identifier.doi | 10.1089/ars.2016.6869 | |
dc.identifier.uri | http://hdl.handle.net/10871/28809 | |
dc.language.iso | en | en_GB |
dc.publisher | Mary Ann Liebert | en_GB |
dc.rights | © Dina Vara et al., 2017; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
dc.title | Direct activation of NADPH oxidase 2 by 2-deoxyribose-1-phosphate triggers nuclear factor kappa B-dependent angiogenesis | en_GB |
dc.type | Article | en_GB |
dc.identifier.issn | 1523-0864 | |
pubs.declined | 2017-08-07T11:53:00.524+0100 | |
dc.description | This is the author accepted manuscript. The final version is available from Mary Ann Liebert via the DOI in this record | en_GB |
dc.identifier.journal | Antioxidants and Redox Signaling | en_GB |