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Research Article25 April 2013Open Access

PHD2 regulates arteriogenic macrophages through TIE2 signalling

Alexander Hamm

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

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Lorenzo Veschini

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

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Yukiji Takeda

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium

Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, KU Leuven, Leuven, Belgium

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Sandra Costa

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

Life and Health Sciences Research Institute, Minho University, Braga, Portugal

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Estelle Delamarre

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

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Mario Leonardo Squadrito

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

Angiogenesis and Tumor Targeting Unit, and HSR‐TIGET, San Raffaele Scientific Institute, Milan, Italy

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Anne‐Theres Henze

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

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Mathias Wenes

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

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Jens Serneels

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

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Ferdinando Pucci

Angiogenesis and Tumor Targeting Unit, and HSR‐TIGET, San Raffaele Scientific Institute, Milan, Italy

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Carmen Roncal

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium

Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, KU Leuven, Leuven, Belgium

Atherosclerosis Research Laboratory, CIMA‐University of Navarra, Pamplona, Spain

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Andrey Anisimov

Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

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Kari Alitalo

Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

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Michele De Palma

Corresponding Author

E-mail address: [email protected]

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

Angiogenesis and Tumor Targeting Unit, and HSR‐TIGET, San Raffaele Scientific Institute, Milan, Italy

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Massimiliano Mazzone

Corresponding Author

E-mail address: [email protected]‐kuleuven.be

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

Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium

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  • Alexander Hamm1,2,‡,
  • Lorenzo Veschini1,2,‡,
  • Yukiji Takeda1,2,3,4,
  • Sandra Costa1,2,5,
  • Estelle Delamarre1,2,
  • Mario Leonardo Squadrito6,7,
  • Anne‐Theres Henze1,2,
  • Mathias Wenes1,2,
  • Jens Serneels1,2,
  • Ferdinando Pucci7,
  • Carmen Roncal1,2,3,4,8,
  • Andrey Anisimov9,
  • Kari Alitalo9,
  • Michele De Palma *,6,7 and
  • Massimiliano Mazzone *,1,2
  • Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
  • Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium
  • Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium
  • Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, KU Leuven, Leuven, Belgium
  • Life and Health Sciences Research Institute, Minho University, Braga, Portugal
  • The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
  • Angiogenesis and Tumor Targeting Unit, and HSR‐TIGET, San Raffaele Scientific Institute, Milan, Italy
  • Atherosclerosis Research Laboratory, CIMA‐University of Navarra, Pamplona, Spain
  • Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
  • ‡

    These authors contributed equally to this work.

*Michele De Palma, Tel: +41 21 6937271; Fax: +41 21 6937210Massimiliano Mazzone, Tel: +32 16 373213; Fax: +32 16 372585

EMBO Mol Med (2013)5:843-857https://doi.org/10.1002/emmm.201302695
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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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