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| Item Type: | Article |
|---|---|
| Title: | Control of endothelial quiescence by FOXO-regulated metabolites |
| Creators Name: | Andrade, J., Shi, C., Costa, A.S.H., 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. and Potente, M. |
| 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: | Cell Proliferation, Endothelial Cells, Forkhead Box Protein O1, Gene Expression Regulation, Glutarates, Human Umbilical Vein Endothelial Cells, Metabolism, Physiologic Neovascularization, Proto-Oncogene Proteins c-akt, Signal Transduction, Valerates, Animals, Mice |
| Source: | Nature Cell Biology |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Volume: | 23 |
| Page Range: | 413-423 |
| Date: | April 2021 |
| Official Publication: | https://doi.org/10.1038/s41556-021-00637-6 |
| PubMed: | View item in PubMed |
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