PHD2 regulates arteriogenic macrophages through TIE2 signalling

Alexander Hamm, Lorenzo Veschini, Yukiji Takeda, Sandra Costa, Estelle Delamarre, Mario Leonardo Squadrito, Anne Theres Henze, Mathias Wenes, Jens Serneels, Ferdinando Pucci, Carmen Roncal, Andrey Anisimov, Kari Alitalo, Michele De Palma, Massimiliano Mazzone

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)843-857
Number of pages15
JournalEMBO Molecular Medicine
Volume5
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Arteriogenesis
  • Ischaemia
  • Macrophages
  • PHD2
  • TIE2

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint Dive into the research topics of 'PHD2 regulates arteriogenic macrophages through TIE2 signalling'. Together they form a unique fingerprint.

  • Cite this

    Hamm, A., Veschini, L., Takeda, Y., Costa, S., Delamarre, E., Squadrito, M. L., Henze, A. T., Wenes, M., Serneels, J., Pucci, F., Roncal, C., Anisimov, A., Alitalo, K., De Palma, M., & Mazzone, M. (2013). PHD2 regulates arteriogenic macrophages through TIE2 signalling. EMBO Molecular Medicine, 5(6), 843-857. https://doi.org/10.1002/emmm.201302695