Journal
EMBO JOURNAL
Volume 36, Issue 16, Pages 2334-2352Publisher
WILEY
DOI: 10.15252/embj.201695518
Keywords
angiogenesis; asparagine; endothelial cell; glutamine; metabolism
Categories
Funding
- EMBO long-term fellowship [EMBO ALTF 306-2014]
- Marie Curie-IEF Fellowship
- Lymphatic Education & Research Network and the Fat Disorders Research Society (LERN/FDRS)
- Leopoldina Postdoc Scholarship-German National Academy of Sciences
- Fonds voor Wetenschappelijk Onderzoek (FWO)
- Agentschap voor Innovatie door Wetenschap en Technologie (IWT)
- FWO [KAN 1.5.184.14, G.0598.12N, G.0532.10, G.0817.11, G.0598.12, G.0834.13, 1.5.202.10N, G.0764.10N]
- Stichting tegen Kanker [2012-177]
- Federal Government Belgium [IUAP7/03]
- Flemish Government, a Concerted Research Activities Belgium [GOA2006/11]
- Foundation against Cancer
- ERC Advanced Research Grant [EU-ERC269073]
- British Heart Foundation Intermediate Clinical Fellowship [FS/12/80/29821]
- British Heart Foundation [FS/12/80/29821] Funding Source: researchfish
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Endothelial cell (EC) metabolism is emerging as a regulator of angiogenesis, but the precise role of glutamine metabolism in ECs is unknown. Here, we show that depriving ECs of glutamine or inhibiting glutaminase 1 (GLS1) caused vessel sprouting defects due to impaired proliferation and migration, and reduced pathological ocular angiogenesis. Inhibition of glutamine metabolism in ECs did not cause energy distress, but impaired tricarboxylic acid (TCA) cycle anaplerosis, macromolecule production, and redox homeostasis. Only the combination of TCA cycle replenishment plus asparagine supplementation restored the metabolic aberrations and proliferation defect caused by glutamine deprivation. Mechanistically, glutamine provided nitrogen for asparagine synthesis to sustain cellular homeostasis. While ECs can take up asparagine, silencing asparagine synthetase (ASNS, which converts glutamine-derived nitrogen and aspartate to asparagine) impaired EC sprouting even in the presence of glutamine and asparagine. Asparagine further proved crucial in glutamine-deprived ECs to restore protein synthesis, suppress ER stress, and reactivate mTOR signaling. These findings reveal a novel link between endothelial glutamine and asparagine metabolism in vessel sprouting.
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