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Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production
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 fac...
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Published in: | Cell 2018-03, Vol.173 (1), p.117-129.e14 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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.
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•Sulfur amino acid (SAA) restriction triggers angiogenesis independent of hypoxia or HIF1α•GCN2/ATF4 pathway regulates VEGF and CGL expression upon SAA restriction in ECs•CGL is required for skeletal muscle angiogenesis activated by diet or exercise•H2S triggers glucose uptake, glycolysis, and PPP concomitant with OXPHOS inhibition in ECs
Restricting dietary sulfur amino acids can trigger angiogenesis and improve vascular health. |
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ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2018.03.001 |