Journal Article

FOXO1 couples metabolic activity and growth state in the vascular endothelium

Lim, Radiance, Braun, Thomas, Happel, Katharina, Fruttiger, Marcus, Boettger, Thomas, Brüning, Jens C., Rajewsky, Klaus, Schoors, Sandra, Aspalter, Irene M., Eelen, Guy, Franco, Claudio A., Zimmermann, Barbara, Potente, Michael, Wilhelm, Kerstin, Keller, Charles, Oellerich, Mark F., Carmeliet, Peter, Gerhardt, Holger

2016

Overview

The transcription factor FOXO1 is identified as a crucial checkpoint of vascular growth, coupling the metabolic and proliferative activities of endothelial cells. FOXO1 is a checkpoint of vascular growth The mechanisms that balance the metabolism of endothelial cells and their growth state are not known. Here Michael Potente and colleagues identify the transcription factor FOXO1 as a crucial checkpoint of vascular growth, coupling the metabolic and proliferative activities of endothelial cells. They find that FOXO1 expression in endothelial cells is required to keep the cells quiescent, through suppressing c-MYC signalling, thereby reducing glycolysis and mitochondrial respiration. Endothelial-specific deletion of FOXO1 in mice induces vessel hyperplasia and enlargement. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136/16 / 631/443/592/16 / Analysis / Animals / Bioenergetics / Cell Proliferation / Cell Respiration / Endothelium / Endothelium, Vascular - cytology / Endothelium, Vascular - growth & development / Endothelium, Vascular - metabolism / Female / Forkhead Box Protein O1 / Forkhead Transcription Factors - deficiency / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Genotype & phenotype / Glucose metabolism / Glycolysis / Growth / Human Umbilical Vein Endothelial Cells - cytology / Human Umbilical Vein Endothelial Cells - metabolism / Humanities and Social Sciences / Humans / Influence / Kinases / letter / Male / Metabolism / Mice / Mice, Inbred C57BL / multidisciplinary / Phosphorylation / Physiological aspects / Physiological research / Proto-Oncogene Proteins c-myc - deficiency / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Respiration / Science / Signal Transduction / Transcription factors / Vascular endothelium