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PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
CNIC, Vasc Pathophysiol, Melchor Fernandez Almagro 3, Madrid 28029, Spain;Queen Marys Univ London, Johns Vane Ctr, Barts Canc Inst, Tumour Biol Dept, Charterhouse Sq, London EC1M 6BQ, England.
CNIC, Vasc Pathophysiol, Melchor Fernandez Almagro 3, Madrid 28029, Spain;CSIC, CIB, Ramiro de Maeztu 9, Madrid 28040, Spain.
Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, E-28049 Madrid, Spain.
CNIC, Myocardial Pathol Areas, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
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2019 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 15022Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

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NATURE PUBLISHING GROUP , 2019. Vol. 9, artikkel-id 15022
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Identifikatorer
URN: urn:nbn:se:uu:diva-396701DOI: 10.1038/s41598-019-50866-xISI: 000491226200005PubMedID: 31636306OAI: oai:DiVA.org:uu-396701DiVA, id: diva2:1368888
Forskningsfinansiär
Knut and Alice Wallenberg FoundationTilgjengelig fra: 2019-11-08 Laget: 2019-11-08 Sist oppdatert: 2019-11-08bibliografisk kontrollert

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