Control of endothelial quiescence by FOXO-regulated metabolites


  • J. Andrade
  • C. Shi
  • A.S.H. Costa
  • J. Choi
  • J. Kim
  • A. Doddaballapur
  • T. Sugino
  • Y.T. Ong
  • M. Castro
  • B. Zimmermann
  • M. Kaulich
  • S. Guenther
  • K. Wilhelm
  • Y. Kubota
  • T. Braun
  • G.Y. Koh
  • A.R. Grosso
  • C. Frezza
  • M. Potente


  • Nature Cell Biology


  • Nat Cell Biol 23: 413-423


  • Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium.