Bruns, AF;
Yuldasheva, N;
Latham, AM;
Bao, L;
Pellet-Many, C;
Frankel, P;
Stephen, SL;
... Ponnambalam, S; + view all
(2012)
A Heat-Shock Protein Axis Regulates VEGFR2 Proteolysis, Blood Vessel Development and Repair.
PLOS ONE
, 7
(11)
, Article e48539. 10.1371/journal.pone.0048539.
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Abstract
Vascular endothelial growth factor A (VEGF-A) binds to the VEGFR2 receptor tyrosine kinase, regulating endothelial function, vascular physiology and angiogenesis. However, the mechanism underlying VEGFR2 turnover and degradation in this response is unclear. Here, we tested a role for heat-shock proteins in regulating the presentation of VEGFR2 to a degradative pathway. Pharmacological inhibition of HSP90 stimulated VEGFR2 degradation in primary endothelial cells and blocked VEGF-A-stimulated intracellular signaling via VEGFR2. HSP90 inhibition stimulated the formation of a VEGFR2-HSP70 complex. Clathrin-mediated VEGFR2 endocytosis is required for this HSP-linked degradative pathway for targeting VEGFR2 to the endosome-lysosome system. HSP90 perturbation selectively inhibited VEGF-A-stimulated human endothelial cell migration in vitro. A mouse femoral artery model showed that HSP90 inhibition also blocked blood vessel repair in vivo consistent with decreased endothelial regeneration. Depletion of either HSP70 or HSP90 caused defects in blood vessel formation in a transgenic zebrafish model. We conclude that perturbation of the HSP70-HSP90 heat-shock protein axis stimulates degradation of endothelial VEGFR2 and modulates VEGF-A-stimulated intracellular signaling, endothelial cell migration, blood vessel development and repair.
| Type: | Article |
|---|---|
| Title: | A Heat-Shock Protein Axis Regulates VEGFR2 Proteolysis, Blood Vessel Development and Repair |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0048539 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0048539 |
| Language: | English |
| Additional information: | © 2012 Bruns et al. 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 author and source are credited. This study was funded by the Wellcome Trust (SP), the British Heart Foundaton (SP, MTK, IZ), a BBSRC-CASE PhD Studentship Award (AML) and a University of Leeds ORSAS Tetley & Lupton PhD Scholarship (LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1381717 |
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