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FOXO1 couples metabolic activity and growth state in the vascular endothelium

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Item Type:Article
Title:FOXO1 couples metabolic activity and growth state in the vascular endothelium
Creators Name:Wilhelm, K. and Happel, K. and Eelen, G. and Schoors, S. and Oellerich, M.F. and Lim, R. and Zimmermann, B. and Aspalter, I.M. and Franco, C.A. and Boettger, T. and Braun, T. and Fruttiger, M. and Rajewsky, K. and Keller, C. and Brüning, J.C. and Gerhardt, H. and Carmeliet, P. and Potente, M.
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.
Keywords:Cell Proliferation, Cell Respiration, Forkhead Transcription Factors, Glycolysis, Human Umbilical Vein Endothelial Cells, Inbred C57BL Mice, Proto-Oncogene Proteins c-myc, Signal Transduction, Vascular Endothelium, Animals, Mice
Publisher:Nature Publishing Group
Page Range:216-220
Date:14 January 2016
Official Publication:https://doi.org/10.1038/nature16498
PubMed:View item in PubMed

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