title: PHD2 regulates arteriogenic macrophages through TIE2 signalling.
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.
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hamm
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Veschini
authors.forename: Yukiji
authors.initials: Y
authors.lastname: Takeda
authors.forename: Sandra
authors.initials: S
authors.lastname: Costa
authors.forename: Estelle
authors.initials: E
authors.lastname: Delamarre
authors.forename: Mario Leonardo
authors.initials: ML
authors.lastname: Squadrito
authors.forename: Anne-Theres
authors.initials: AT
authors.lastname: Henze
authors.forename: Mathias
authors.initials: M
authors.lastname: Wenes
authors.forename: Jens
authors.initials: J
authors.lastname: Serneels
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Pucci
authors.forename: Carmen
authors.initials: C
authors.lastname: Roncal
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D020868:Gene Silencing; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D035683:MicroRNAs; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse