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

28 Citations (Scopus)

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 1 2013
Externally publishedYes

Fingerprint

Prolyl Hydroxylases
Macrophages
Angiopoietin-1
Phenotype
Collateral Circulation
Gene Silencing
Femoral Artery
Protein Domains
Skeletal Muscle
Necrosis
Down-Regulation
Growth

Keywords

  • Arteriogenesis
  • Ischaemia
  • Macrophages
  • PHD2
  • TIE2

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Hamm, A., Veschini, L., Takeda, Y., Costa, S., Delamarre, E., Squadrito, M. L., ... Mazzone, M. (2013). PHD2 regulates arteriogenic macrophages through TIE2 signalling. EMBO Molecular Medicine, 5(6), 843-857. https://doi.org/10.1002/emmm.201302695

PHD2 regulates arteriogenic macrophages through TIE2 signalling. / Hamm, Alexander; Veschini, Lorenzo; Takeda, Yukiji; Costa, Sandra; Delamarre, Estelle; Squadrito, Mario Leonardo; Henze, Anne Theres; Wenes, Mathias; Serneels, Jens; Pucci, Ferdinando; Roncal, Carmen; Anisimov, Andrey; Alitalo, Kari; De Palma, Michele; Mazzone, Massimiliano.

In: EMBO Molecular Medicine, Vol. 5, No. 6, 01.06.2013, p. 843-857.

Research output: Contribution to journalArticle

Hamm, A, Veschini, L, Takeda, Y, Costa, S, Delamarre, E, Squadrito, ML, Henze, AT, 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, vol. 5, no. 6, pp. 843-857. https://doi.org/10.1002/emmm.201302695
Hamm A, Veschini L, Takeda Y, Costa S, Delamarre E, Squadrito ML et al. PHD2 regulates arteriogenic macrophages through TIE2 signalling. EMBO Molecular Medicine. 2013 Jun 1;5(6):843-857. https://doi.org/10.1002/emmm.201302695
Hamm, Alexander ; Veschini, Lorenzo ; Takeda, Yukiji ; Costa, Sandra ; Delamarre, Estelle ; Squadrito, Mario Leonardo ; Henze, Anne Theres ; Wenes, Mathias ; Serneels, Jens ; Pucci, Ferdinando ; Roncal, Carmen ; Anisimov, Andrey ; Alitalo, Kari ; De Palma, Michele ; Mazzone, Massimiliano. / PHD2 regulates arteriogenic macrophages through TIE2 signalling. In: EMBO Molecular Medicine. 2013 ; Vol. 5, No. 6. pp. 843-857.
@article{d656826d8a2343e58c79820f4e36d3eb,
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.",
keywords = "Arteriogenesis, Ischaemia, Macrophages, PHD2, TIE2",
author = "Alexander Hamm and Lorenzo Veschini and Yukiji Takeda and Sandra Costa and Estelle Delamarre and Squadrito, {Mario Leonardo} and Henze, {Anne Theres} and Mathias Wenes and Jens Serneels and Ferdinando Pucci and Carmen Roncal and Andrey Anisimov and Kari Alitalo and {De Palma}, Michele and Massimiliano Mazzone",
year = "2013",
month = "6",
day = "1",
doi = "10.1002/emmm.201302695",
language = "English (US)",
volume = "5",
pages = "843--857",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - PHD2 regulates arteriogenic macrophages through TIE2 signalling

AU - Hamm, Alexander

AU - Veschini, Lorenzo

AU - Takeda, Yukiji

AU - Costa, Sandra

AU - Delamarre, Estelle

AU - Squadrito, Mario Leonardo

AU - Henze, Anne Theres

AU - Wenes, Mathias

AU - Serneels, Jens

AU - Pucci, Ferdinando

AU - Roncal, Carmen

AU - Anisimov, Andrey

AU - Alitalo, Kari

AU - De Palma, Michele

AU - Mazzone, Massimiliano

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

AB - 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.

KW - Arteriogenesis

KW - Ischaemia

KW - Macrophages

KW - PHD2

KW - TIE2

UR - http://www.scopus.com/inward/record.url?scp=84878707647&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878707647&partnerID=8YFLogxK

U2 - 10.1002/emmm.201302695

DO - 10.1002/emmm.201302695

M3 - Article

C2 - 23616286

AN - SCOPUS:84878707647

VL - 5

SP - 843

EP - 857

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 6

ER -