Open AccessPHD2 regulates arteriogenic macrophages through TIE2 signalling
Author(s) -
Hamm Alexander,
Veschini Lorenzo,
Takeda Yukiji,
Costa Sandra,
Delamarre Estelle,
Squadrito Mario Leonardo,
Henze AnneTheres,
Wenes Mathias,
Serneels Jens,
Pucci Ferdinando,
Roncal Carmen,
Anisimov Andrey,
Alitalo Kari,
De Palma Michele,
Mazzone Massimiliano
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201302695
Subject(s) - angiopoietin receptor , arteriogenesis , microbiology and biotechnology , downregulation and upregulation , phenotype , gene silencing , angiopoietin , biology , cancer research , angiogenesis , gene , biochemistry , vascular endothelial growth factor , vegf receptors
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.