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  FOXO1 couples metabolic activity and growth state in the vascular endothelium

Wilhelm, K., Happel, K., Eelen, G., Schoors, S., Oellerich, M. F., Lim, R., et al. (2016). FOXO1 couples metabolic activity and growth state in the vascular endothelium. NATURE, 529(7585), 216-U226. doi:10.1038/nature16498.

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 Creators:
Wilhelm, Kerstin1, Author              
Happel, Katharina, Author
Eelen, Guy, Author
Schoors, Sandra, Author
Oellerich, Mark F., Author
Lim, Radiance, Author
Zimmermann, Barbara, Author
Aspalter, Irene M., Author
Franco, Claudio A., Author
Boettger, Thomas2, Author              
Braun, Thomas2, Author              
Fruttiger, Marcus, Author
Rajewsky, Klaus, Author
Keller, Charles, Author
Bruening, Jens C., Author
Gerhardt, Holger, Author
Carmeliet, Peter, Author
Potente, Michael1, Author              
Affiliations:
1Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591701              
2Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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Free keywords: TRANSCRIPTION FACTOR FKHR; GENE-EXPRESSION; C-MYC; OXIDATIVE STRESS; ANGIOGENESIS; CELLS; MICE; IDENTIFICATION; MAINTENANCE; HOMEOSTASISScience & Technology - Other Topics;
 Abstract: Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements(1). Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation(2,3). Adjusting endothelial metabolism to the growth state is central to normal vessel growth and function(1,4), yet it is poorly understood at the molecular level. Here we report that the forkhead box O (FOXO) transcription factor FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in ECs. Endothelial-restricted deletion of FOXO1 in mice induces a profound increase in EC proliferation that interferes with coordinated sprouting, thereby causing hyperplasia and vessel enlargement. Conversely, forced expression of FOXO1 restricts vascular expansion and leads to vessel thinning and hypobranching. We find that FOXO1 acts as a gatekeeper of endothelial quiescence, which decelerates metabolic activity by reducing glycolysis and mitochondrial respiration. Mechanistically, FOXO1 suppresses signalling by MYC (also known as c-MYC), a powerful driver of anabolic metabolism and growth(5,6). MYC ablation impairs glycolysis, mitochondrial function and proliferation of ECs while its EC-specific overexpression fuels these processes. Moreover, restoration of MYC signalling in FOXO1-overexpressing endothelium normalizes metabolic activity and branching behaviour. Our findings identify FOXO1 as a critical rheostat of vascular expansion and define the FOXO1-MYC transcriptional network as a novel metabolic checkpoint during endothelial growth and proliferation.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000368015700038
DOI: 10.1038/nature16498
 Degree: -

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Title: NATURE
Source Genre: Journal
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Publ. Info: MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND : NATURE PUBLISHING GROUP
Pages: - Volume / Issue: 529 (7585) Sequence Number: - Start / End Page: 216 - U226 Identifier: ISSN: 0028-0836