Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production

Alban Longchamp, Teodelinda Mirabella, Alessandro Arduini, Michael R. MacArthur, Abhirup Das, J. Humberto Treviño-Villarreal, Christopher Hine, Issam Ben-Sahra, Nelson H. Knudsen, Lear E. Brace, Justin Reynolds, Pedro Mejia, Ming Tao, Gaurav Sharma, Rui Wang, Jean Marc Corpataux, Jacques Antoine Haefliger, Kyo Han Ahn, Chih Hao Lee, Brendan D. ManningDavid A. Sinclair, Christopher S. Chen, C. Keith Ozaki, James R. Mitchell*

*Corresponding author for this work

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1α. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1α. We also identified a requirement for cystathionine-γ-lyase in VEGF-dependent angiogenesis via increased hydrogen sulfide (H2S) production. H2S mediated its proangiogenic effects in part by inhibiting mitochondrial electron transport and oxidative phosphorylation, resulting in increased glucose uptake and glycolytic ATP production. Restricting dietary sulfur amino acids can trigger angiogenesis and improve vascular health.

Original languageEnglish (US)
Pages (from-to)117-129.e14
JournalCell
Volume173
Issue number1
DOIs
StatePublished - Mar 22 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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