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

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

来源：Cell, 2018, 173(1): 117-+.

DOI：10.1016/j.cell.2018.03.001

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.

• 出版日期2018-3-22