Role of glutamine and interlinked asparagine metabolism in vessel formation
Open accessAbstract
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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Glutamate supplementation during glutamine deprivation cannot rescue impaired cell growth or mitochondrial respiration, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.
“Although glutamate is the major downstream product of glutamine, glutamate supplementation during glutamine deprivation cannot rescue the impaired cell growth or mitochondrial respiration16,43–45, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [44]
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Canagliflozin Inhibits Human Endothelial Cell Proliferation and Tube Formation
Behnammanesh, G., Durante, Z. E., Peyton, K. J., Martinez-Lemus, L. A., Brown, S. M., Bender, S. B., & Durante, W. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00362 · Cited by 61 · see citing works
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- Authors
- Huang, H., Vandekeere, S., Kalucka, J., Bierhansl, L., Zecchin, A., Brüning, U., Visnagri, A., Yuldasheva, N., Goveia, J., Cruys, B., Brepoels, K., Wyns, S., Rayport, S., Ghesquière, B., Vinckier, S., Schoonjans, L., Cubbon, R., Dewerchin, M., Eelen, G., & Carmeliet, P.
- Affiliations
- VIB-KU Leuven Center for Cancer Biology (BE)
- University of Leeds (GB)
- New York State Psychiatric Institute (US)
- Corresponding author
- Carmeliet, Peter
- ORCID
- Venue
- The EMBO Journal
- Published
- 2017-06-29
- Volume
- 36
- Issue
- 16
- Pages
- 2334-2352
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5556263
- OpenAlex
- W2729019185
- Cited by
- 320
- References
- 87
- Citations by year
- 2026: 26 · 2025: 41 · 2024: 41 · 2023: 28 · 2022: 54 · 2021: 39 · 2020: 31 · 2019: 28 · 2018: 23 · 2017: 8
- FWCI
- 10.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- European Molecular Biology Organization (ALTF 306‐2014)
- Federal Government Belgium (IUAP7/03)
- Flemish Government Methusalem Funding
- Concerted Research Activities Belgium (GOA2006/11)
- ERC (EU‐ERC269073)
- British Heart Foundation (FS/12/80/29821)
- Marie Curie‐IEF
- Lymphatic Education & Research Network
- Fat Disorders Research Society
- German National Academy of Sciences
- Fonds Wetenschappelijk Onderzoek (KAN 1.5.184.14, G.0532.10, G.0817.11, G.0598.12, G.0834.13, 1.5.202.10N, G.0764.10N)
- Agentschap voor Innovatie door Wetenschap en Technologie
- Stichting Tegen Kanker (2012‐177)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- glutamine metabolism, asparagine metabolism, endothelial cells, angiogenesis, vessel sprouting, GLS1, asparagine synthetase, TCA cycle anaplerosis, redox homeostasis, protein synthesis, endoplasmic reticulum stress, mTOR signaling, endothelial cell proliferation and migration
- MeSH terms
- Asparagine, Cell Movement, Culture Media, Glutaminase, Glutamine, Humans, Neovascularization, Pathologic, Neovascularization, Physiologic, Endothelial Cells, Cell Proliferation, Metabolic Networks and Pathways, Human Umbilical Vein Endothelial Cells
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