PHD2 regulates arteriogenic macrophages through TIE2 signaling
Main Author: | |
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Publication Date: | 2013 |
Other Authors: | , , , , , , , , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/1822/24885 |
Summary: | 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. |
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PHD2 regulates arteriogenic macrophages through TIE2 signalingArteriogenesisIschaemiaMacrophagesPHD2TIE2Science & TechnologyOcclusion 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.The authors thank Y. Jonsson for technical assistance. The authors are thankful to P. Carmeliet for scientific discussion and support. AH was granted by Deutsche Forschungsgemeinschaft (DFG), LV by the European Society of Cardiology (ESC), SC by Fundacao para a Ciencia e a Tecnologia (FCT), ED by Fondation ARC pour la recherche sur le cancer, A-T.H by Fonds Wetenschappelijk Onderzoek (FWO). This work was supported by grants from the Fonds Wetenschappelijk Onderzoek (FWO G.0726.10 to MM) and the European Research Council (OxyMO to MM and Tie2<SUP>+</SUP> Monocytes to MDP).John Wiley and SonsUniversidade do MinhoHamm, AlexanderVeschini, LorenzoTakeda, YukijiCosta, Sandra Maria Araújo daDelamarre, EstelleSquadrito, Mario LeonardoHenze, Anne-TheresWenes, MathiasSerneels, JensPucci, FerdinandoRoncal, CarmenAnisimov, AndreyAlitalo, KariDe Palma, MicheleMazzone, Massimiliano20132013-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/24885eng1757-467610.1002/emmm.20130269523616286www.onlinelibrary.wiley.cominfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:24:06Zoai:repositorium.sdum.uminho.pt:1822/24885Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:18:00.727969Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
PHD2 regulates arteriogenic macrophages through TIE2 signaling |
title |
PHD2 regulates arteriogenic macrophages through TIE2 signaling |
spellingShingle |
PHD2 regulates arteriogenic macrophages through TIE2 signaling Hamm, Alexander Arteriogenesis Ischaemia Macrophages PHD2 TIE2 Science & Technology |
title_short |
PHD2 regulates arteriogenic macrophages through TIE2 signaling |
title_full |
PHD2 regulates arteriogenic macrophages through TIE2 signaling |
title_fullStr |
PHD2 regulates arteriogenic macrophages through TIE2 signaling |
title_full_unstemmed |
PHD2 regulates arteriogenic macrophages through TIE2 signaling |
title_sort |
PHD2 regulates arteriogenic macrophages through TIE2 signaling |
author |
Hamm, Alexander |
author_facet |
Hamm, Alexander Veschini, Lorenzo Takeda, Yukiji Costa, Sandra Maria Araújo da 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 |
author_role |
author |
author2 |
Veschini, Lorenzo Takeda, Yukiji Costa, Sandra Maria Araújo da 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 |
author2_role |
author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Hamm, Alexander Veschini, Lorenzo Takeda, Yukiji Costa, Sandra Maria Araújo da 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 |
dc.subject.por.fl_str_mv |
Arteriogenesis Ischaemia Macrophages PHD2 TIE2 Science & Technology |
topic |
Arteriogenesis Ischaemia Macrophages PHD2 TIE2 Science & Technology |
description |
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. |
publishDate |
2013 |
dc.date.none.fl_str_mv |
2013 2013-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/24885 |
url |
http://hdl.handle.net/1822/24885 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1757-4676 10.1002/emmm.201302695 23616286 www.onlinelibrary.wiley.com |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
John Wiley and Sons |
publisher.none.fl_str_mv |
John Wiley and Sons |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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