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Role of glutamine and interlinked asparagine metabolism in vessel formation
Author(s) -
Huang Hongling,
Vandekeere Saar,
Kalucka Joanna,
Bierhansl Laura,
Zecchin Annalisa,
Brüning Ulrike,
Visnagri Asjad,
Yuldasheva Nadira,
Goveia Jermaine,
Cruys Bert,
Brepoels Katleen,
Wyns Sabine,
Rayport Stephen,
Ghesquière Bart,
Vinckier Stefan,
Schoonjans Luc,
Cubbon Richard,
Dewerchin Mieke,
Eelen Guy,
Carmeliet Peter
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695518
Subject(s) - glutamine , asparagine , biology , asparagine synthetase , citric acid cycle , biochemistry , metabolism , glutaminase , angiogenesis , microbiology and biotechnology , amino acid , cancer research
Endothelial cell ( EC ) metabolism is emerging as a regulator of angiogenesis, but the precise role of glutamine metabolism in EC s is unknown. Here, we show that depriving EC s of glutamine or inhibiting glutaminase 1 ( GLS 1) caused vessel sprouting defects due to impaired proliferation and migration, and reduced pathological ocular angiogenesis. Inhibition of glutamine metabolism in EC s 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 EC s 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 EC s 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.