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

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Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production.
Cell ( IF 45.5 ) Pub Date : 2018-Mar-22 , DOI: 10.1016/j.cell.2018.03.001
Alban Longchamp ₁ , Teodelinda Mirabella ₂ , Alessandro Arduini ₃ , Michael R MacArthur ₃ , Abhirup Das ₄ , J Humberto Treviño-Villarreal ₃ , Christopher Hine ₃ , Issam Ben-Sahra ₃ , Nelson H Knudsen ₃ , Lear E Brace ₃ , Justin Reynolds ₃ , Pedro Mejia ₃ , Ming Tao ₅ , Gaurav Sharma ₅ , Rui Wang ₆ , Jean-Marc Corpataux ₇ , Jacques-Antoine Haefliger ₇ , Kyo Han Ahn ₈ , Chih-Hao Lee ₃ , Brendan D Manning ₃ , David A Sinclair ₄ , Christopher S Chen ₂ , C Keith Ozaki ₅ , James R Mitchell ₃

Affiliation

Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Surgery and the Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
Tissue Microfabrication Lab, Department of Biomedical Engineering, Boston University, Boston, MA, USA; Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Glenn Center for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney NSW 2052, Australia.
Department of Surgery and the Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON, Canada.
Department of Vascular Surgery, Laboratory of Experimental Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Department of Chemistry, Postech, 77 Cheongam-Ro, Nam-Gu, Pohang, 37673, Republic of Korea.

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.

中文翻译：

氨基酸限制通过GCN2 / ATF4调节VEGF和H2S产生来触发血管生成。

血管生成是由内皮细胞（EC）形成的新血管，是对缺血或运动后由血管内皮生长因子（VEGF）策划的氧/营养剥夺的适应性反应。缺氧是通过转录因子HIF1α引起的VEGF表达的最容易理解的触发因素。营养不足与缺血过程中的缺氧密不可分，但其在血管生成中的作用尚不明确。在这里，我们确定了硫氨基酸的限制是促血管生成的触发因素，通过独立于缺氧或HIF1α。₂ S）生产。H ₂ S部分通过抑制线粒体电子运输和氧化磷酸化来介导其促血管生成作用，从而导致葡萄糖摄取增加和糖酵解ATP产生。

更新日期：2018-03-22

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