Role of Glutamine and Interlinked Asparagine Metabolism in Vessel Formation

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2017 Jun 30

PMID 28659375

Citations 147

Authors

Hongling Huang

Saar Vandekeere

Joanna Kalucka

Laura Bierhansl

Annalisa Zecchin

Ulrike Bruning

Asjad Visnagri

Nadira Yuldasheva

Jermaine Goveia

Bert Cruys

Katleen Brepoels

Sabine Wyns

Stephen Rayport

Bart Ghesquiere

Stefan Vinckier

Luc Schoonjans

Richard Cubbon

Mieke Dewerchin

Guy Eelen

Peter Carmeliet

Affiliations

Soon will be listed here.

Abstract

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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