Control of endothelial quiescence by FOXO-regulated metabolites.
Details
Serval ID
serval:BIB_FD68345F21FB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Control of endothelial quiescence by FOXO-regulated metabolites.
Journal
Nature cell biology
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
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 15:54
Last modification date
11/01/2022 13:58