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Nature. 2016 Jan 14;529(7585):216-20. doi: 10.1038/nature16498. Epub 2016 Jan 6.

FOXO1 couples metabolic activity and growth state in the vascular endothelium.

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Angiogenesis &Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium.
Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
Vascular Morphogenesis Laboratory, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon 1649-028, Portugal.
Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
Max Delbrück Center for Molecular Medicine (MDC), D-13125 Berlin, Germany.
Children's Cancer Therapy Development Institute, Beaverton, Oregon 97005, USA.
Max Planck Institute for Metabolism Research, Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University of Cologne, D-50931 Cologne, Germany.
Vascular Patterning Laboratory, Vesalius Research Center, VIB and University of Leuven, Leuven 3000, Belgium.
DZHK (German Center for Cardiovascular Research), partner site Berlin, D-13347 Berlin, Germany.
Berlin Institute of Health (BIH), D-10117 Berlin, Germany.
International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
DZHK (German Center for Cardiovascular Research), partner site Frankfurt Rhine-Main, D-13347 Berlin, Germany.


Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements. Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation. Adjusting endothelial metabolism to the growth state is central to normal vessel growth and function, 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. 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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