PHD2 regulates arteriogenic macrophages through TIE2 signalling

Authors

  • Alexander Hamm,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
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    • These authors contributed equally to this work.

  • Lorenzo Veschini,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
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    • These authors contributed equally to this work.

  • Yukiji Takeda,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
    3. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium
    4. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, KU Leuven, Leuven, Belgium
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  • Sandra Costa,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
    3. Life and Health Sciences Research Institute, Minho University, Braga, Portugal
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  • Estelle Delamarre,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
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  • Mario Leonardo Squadrito,

    1. The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
    2. Angiogenesis and Tumor Targeting Unit, and HSR-TIGET, San Raffaele Scientific Institute, Milan, Italy
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  • Anne-Theres Henze,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
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  • Mathias Wenes,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
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  • Jens Serneels,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
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  • Ferdinando Pucci,

    1. Angiogenesis and Tumor Targeting Unit, and HSR-TIGET, San Raffaele Scientific Institute, Milan, Italy
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  • Carmen Roncal,

    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
    3. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium
    4. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, KU Leuven, Leuven, Belgium
    5. Atherosclerosis Research Laboratory, CIMA-University of Navarra, Pamplona, Spain
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  • Andrey Anisimov,

    1. Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
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  • Kari Alitalo,

    1. Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
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  • Michele De Palma,

    Corresponding author
    1. The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
    2. Angiogenesis and Tumor Targeting Unit, and HSR-TIGET, San Raffaele Scientific Institute, Milan, Italy
    • Michele De Palma, Tel: +41 21 6937271; Fax: +41 21 6937210

      Massimiliano Mazzone, Tel: +32 16 373213; Fax: +32 16 372585

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  • Massimiliano Mazzone

    Corresponding author
    1. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    2. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
    • Michele De Palma, Tel: +41 21 6937271; Fax: +41 21 6937210

      Massimiliano Mazzone, Tel: +32 16 373213; Fax: +32 16 372585

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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

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