These authors contributed equally to this work.
PHD2 regulates arteriogenic macrophages through TIE2 signalling
Version of Record online: 25 APR 2013
Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 6, pages 843–857, June 2013
How to Cite
Hamm, A., Veschini, L., Takeda, Y., Costa, S., Delamarre, E., Squadrito, M. L., Henze, A.-T., Wenes, M., Serneels, J., Pucci, F., Roncal, C., Anisimov, A., Alitalo, K., De Palma, M. and Mazzone, M. (2013), PHD2 regulates arteriogenic macrophages through TIE2 signalling. EMBO Mol Med, 5: 843–857. doi: 10.1002/emmm.201302695
- Issue online: 4 JUN 2013
- Version of Record online: 25 APR 2013
- Manuscript Accepted: 12 MAR 2013
- Manuscript Revised: 9 MAR 2013
- Manuscript Received: 28 FEB 2013
Occlusion of the main arterial route redirects blood flow to the collateral circulation. We previously reported that macrophages genetically modified to express low levels of prolyl hydroxylase domain protein 2 (PHD2) display an arteriogenic phenotype, which promotes the formation of collateral vessels and protects the skeletal muscle from ischaemic necrosis. However, the molecular mechanisms underlying this process are unknown. Here, we demonstrate that femoral artery occlusion induces a switch in macrophage phenotype through angiopoietin-1 (ANG1)-mediated Phd2 repression. ANG blockade by a soluble trap prevented the downregulation of Phd2 expression in macrophages and their phenotypic switch, thus inhibiting collateral growth. ANG1-dependent Phd2 repression initiated a feed-forward loop mediated by the induction of the ANG receptor TIE2 in macrophages. Gene silencing and cell depletion strategies demonstrate that TIE2 induction in macrophages is required to promote their proarteriogenic functions, enabling collateral vessel formation following arterial obstruction. These results indicate an indispensable role for TIE2 in sustaining in situ programming of macrophages to a proarteriogenic, M2-like phenotype, suggesting possible new venues for the treatment of ischaemic disorders.