Control of endothelial quiescence by FOXO-regulated metabolites.

Details

Serval ID
serval:BIB_FD68345F21FB
Type
Article: article from journal or magazin.
Collection
Publications
Title
Control of endothelial quiescence by FOXO-regulated metabolites.
Journal
Nature cell biology
Author(s)
Andrade J., Shi C., Costa ASH, Choi J., Kim J., Doddaballapur A., Sugino T., Ong Y.T., Castro M., Zimmermann B., Kaulich M., Guenther S., Wilhelm K., Kubota Y., Braun T., Koh G.Y., Grosso A.R., Frezza C., Potente M.
ISSN
1476-4679 (Electronic)
ISSN-L
1465-7392
Publication state
Published
Issued date
04/2021
Peer-reviewed
Oui
Volume
23
Number
4
Pages
413-423
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
24/04/2021 14:54
Last modification date
28/09/2021 5:58
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