title: FOXO1 couples metabolic activity and growth state in the vascular endothelium.
abstract: 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.
authors.affiliation: Angiogenesis &Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wilhelm
authors.affiliation: Angiogenesis &Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Happel
authors.affiliation: 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.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schoors
authors.affiliation: Angiogenesis &Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Oellerich
authors.affiliation: Angiogenesis &Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
authors.forename: Radiance
authors.initials: R
authors.lastname: Lim
authors.affiliation: Angiogenesis &Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zimmermann
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Aspalter
authors.affiliation: Vascular Morphogenesis Laboratory, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon 1649-028, Portugal.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Franco
authors.affiliation: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boettger
authors.affiliation: Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), D-13125 Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.affiliation: Children's Cancer Therapy Development Institute, Beaverton, Oregon 97005, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
authors.affiliation: 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.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.|Max Delbrück Center for Molecular Medicine (MDC), D-13125 Berlin, 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.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Angiogenesis &Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Potente
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D019069:Cell Respiration; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc