PHD2 regulates arteriogenic macrophages through TIE2 signalling

EMBO Molecular Medicine

Alexander Hamm²  Lorenzo Veschini²  Yukiji Takeda²  Sandra Costa²  Estelle Delamarre²  Mario Leonardo Squadrito¹  Anne-Theres Henze²  Mathias Wenes²  Jens Serneels²  Ferdinando Pucci⁵  Carmen Roncal²  Andrey Anisimov⁴  Kari Alitalo⁴  Michele De Palma³ 

[1]The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland

[2]Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium

[3]E-mail address: [4]Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

[5]Angiogenesis and Tumor Targeting Unit, and HSR-TIGET, San Raffaele Scientific Institute, Milan, Italy

关键词: arteriogenesis;    ischaemia;    macrophages;    PHD2;    TIE2;   

DOI  :  10.1002/emmm.201302695

来源: Wiley

【 摘 要 】

Abstract

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.

→See accompanying articles http://dx.doi.org/10.1002/emmm.201302752 and http://dx.doi.org/10.1002/emmm.201302794

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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