PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production

Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow colle...

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Autores: Gomez-Escudero, Jesus, Clemente, Cristina, García-Weber, Diego, Acin-Perez, Rebeca, Millán, Jaime, Enriquez, Jose Antonio, Bentley, Katie, Carmeliet, Peter, Arroyo, Alicia G
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/8541
Acceso en línea:http://hdl.handle.net/20.500.12105/8541
Access Level:acceso abierto
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spelling PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP productionGomez-Escudero, JesusClemente, CristinaGarcía-Weber, DiegoAcin-Perez, RebecaMillán, JaimeEnriquez, Jose AntonioBentley, KatieCarmeliet, PeterArroyo, Alicia GAngiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow collective migration and extension of the sprout while maintaining barrier integrity. All these processes require energy, and the predominant ATP generation route in endothelial cells is glycolysis. However, it remains unclear how ATP reaches the plasma membrane and intercellular junctions. In this study, we demonstrate that the glycolytic enzyme pyruvate kinase 2 (PKM2) is required for sprouting angiogenesis in vitro and in vivo through the regulation of endothelial cell-junction dynamics and collective migration. We show that PKM2-silencing decreases ATP required for proper VE-cadherin internalization/traffic at endothelial cell-cell junctions. Our study provides fresh insight into the role of ATP subcellular compartmentalization in endothelial cells during angiogenesis. Since manipulation of EC glycolysis constitutes a potential therapeutic intervention route, particularly in tumors and chronic inflammatory disease, these findings may help to refine the targeting of endothelial glycolytic activity in disease.Nature Publishing GroupMinisterio de Ciencia, Innovación y Universidades (España)Ministerio de Economía, Industria y Competitividad (España)Knut and Alice Wallenberg FoundationInstituto de Salud Carlos IIIFundación ProCNIC20192019-10-3120192019-10-0120192019-10-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamapplication/octet-streamhttp://hdl.handle.net/20.500.12105/8541reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES SEV-2015-0505 Not availableES SAF2014-52050-R Not availableES SAF2017-83229-R Not availableopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/85412026-06-12T12:43:37Z
dc.title.none.fl_str_mv PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
title PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
spellingShingle PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
Gomez-Escudero, Jesus
title_short PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
title_full PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
title_fullStr PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
title_full_unstemmed PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
title_sort PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
dc.creator.none.fl_str_mv Gomez-Escudero, Jesus
Clemente, Cristina
García-Weber, Diego
Acin-Perez, Rebeca
Millán, Jaime
Enriquez, Jose Antonio
Bentley, Katie
Carmeliet, Peter
Arroyo, Alicia G
author Gomez-Escudero, Jesus
author_facet Gomez-Escudero, Jesus
Clemente, Cristina
García-Weber, Diego
Acin-Perez, Rebeca
Millán, Jaime
Enriquez, Jose Antonio
Bentley, Katie
Carmeliet, Peter
Arroyo, Alicia G
author_role author
author2 Clemente, Cristina
García-Weber, Diego
Acin-Perez, Rebeca
Millán, Jaime
Enriquez, Jose Antonio
Bentley, Katie
Carmeliet, Peter
Arroyo, Alicia G
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Ministerio de Economía, Industria y Competitividad (España)
Knut and Alice Wallenberg Foundation
Instituto de Salud Carlos III
Fundación ProCNIC
description Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow collective migration and extension of the sprout while maintaining barrier integrity. All these processes require energy, and the predominant ATP generation route in endothelial cells is glycolysis. However, it remains unclear how ATP reaches the plasma membrane and intercellular junctions. In this study, we demonstrate that the glycolytic enzyme pyruvate kinase 2 (PKM2) is required for sprouting angiogenesis in vitro and in vivo through the regulation of endothelial cell-junction dynamics and collective migration. We show that PKM2-silencing decreases ATP required for proper VE-cadherin internalization/traffic at endothelial cell-cell junctions. Our study provides fresh insight into the role of ATP subcellular compartmentalization in endothelial cells during angiogenesis. Since manipulation of EC glycolysis constitutes a potential therapeutic intervention route, particularly in tumors and chronic inflammatory disease, these findings may help to refine the targeting of endothelial glycolytic activity in disease.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-10-31
2019
2019-10-01
2019
2019-10-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/8541
url http://hdl.handle.net/20.500.12105/8541
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES SEV-2015-0505 Not available
ES SAF2014-52050-R Not available
ES SAF2017-83229-R Not available
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
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dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
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