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 Manning; David A Sinclair; Christopher S Chen; C Keith Ozaki; James R Mitchell

doi:10.1016/j.cell.2018.03.001

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

Cell. 2018 Mar 22;173(1):117-129.e14. doi: 10.1016/j.cell.2018.03.001.

Authors

Alban Longchamp¹, Teodelinda Mirabella², Alessandro Arduini³, Michael R MacArthur³, Abhirup Das⁴, J Humberto Treviño-Villarreal³, Christopher Hine³, Issam Ben-Sahra³, Nelson H Knudsen³, Lear E Brace³, Justin Reynolds³, Pedro Mejia³, Ming Tao⁵, Gaurav Sharma⁵, Rui Wang⁶, Jean-Marc Corpataux⁷, Jacques-Antoine Haefliger⁷, Kyo Han Ahn⁸, Chih-Hao Lee³, Brendan D Manning³, David A Sinclair⁴, Christopher S Chen², C Keith Ozaki⁵, James R Mitchell⁹

Affiliations

¹ 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.
² Tissue Microfabrication Lab, Department of Biomedical Engineering, Boston University, Boston, MA, USA; Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
³ Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ 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.
⁵ Department of Surgery and the Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON, Canada.
⁷ Department of Vascular Surgery, Laboratory of Experimental Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
⁸ Department of Chemistry, Postech, 77 Cheongam-Ro, Nam-Gu, Pohang, 37673, Republic of Korea.
⁹ Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Activating Transcription Factor 4 / antagonists & inhibitors
Activating Transcription Factor 4 / genetics
Activating Transcription Factor 4 / metabolism*
Amino Acids, Sulfur / deficiency*
Amino Acids, Sulfur / metabolism
Animals
Cystathionine gamma-Lyase / metabolism
Disease Models, Animal
Female
Human Umbilical Vein Endothelial Cells
Humans
Hydrogen Sulfide / metabolism*
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Ischemia / metabolism
Ischemia / pathology
Male
Mice
Mice, Inbred C57BL
Neovascularization, Physiologic
Physical Conditioning, Animal
Protein Serine-Threonine Kinases / metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism*

Substances

Amino Acids, Sulfur
Hypoxia-Inducible Factor 1, alpha Subunit
RNA, Small Interfering
Vascular Endothelial Growth Factor A
Activating Transcription Factor 4
Eif2ak4 protein, mouse
Protein Serine-Threonine Kinases
Cystathionine gamma-Lyase
Hydrogen Sulfide

Abstract

Publication types

MeSH terms

Substances

Grants and funding