Control of endothelial quiescence by FOXO-regulated metabolites

Nat Cell Biol. 2021 Apr;23(4):413-423. doi: 10.1038/s41556-021-00637-6. Epub 2021 Apr 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics*
  • Endothelial Cells / metabolism*
  • Forkhead Box Protein O1 / genetics*
  • Gene Expression Regulation / genetics
  • Glutarates / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Metabolism / genetics
  • Mice
  • Neovascularization, Physiologic / genetics*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / genetics
  • Valerates / metabolism

Substances

  • Forkhead Box Protein O1
  • Glutarates
  • Valerates
  • Proto-Oncogene Proteins c-akt