Journal
CELL
Volume 173, Issue 1, Pages 117-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.03.001
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Funding
- Swiss National Science Foundation [P1LAP3_158895]
- National Science Foundation [NSF-DGE1144152]
- Canadian Institutes of Health Sciences
- NIH [EB00262, AG036712, DK090629]
- American Heart Association [12GRNT9510001, 12GRNT1207025]
- Lea Carpenter du Pont Vascular Surgery Fund
- Carl and Ruth Shapiro Family Foundation
- Charoen Pokphand Group
- Swiss National Science Foundation (SNF) [P1LAP3_158895] Funding Source: Swiss National Science Foundation (SNF)
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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 HIF1 alpha. 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 HIF1 alpha. We also identified a requirement for cystathionine-gamma-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.
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