Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements1. Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation2,3. Adjusting endothelial metabolism to growth state is central to normal vessel growth and function1,4, yet 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 c-MYC (termed MYC hereafter), a powerful driver of anabolic metabolism and growth5,6. 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 normalises 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.

This paper used adenovirus FOXO1-Flag and c-MYC-HA made by Vector Biolabs

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