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

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. ManningDavid A. Sinclair, Christopher S. Chen, C. Keith Ozaki, James R. Mitchell^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

226 Scopus citations

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. Restricting dietary sulfur amino acids can trigger angiogenesis and improve vascular health.

Original language	English (US)
Pages (from-to)	117-129.e14
Journal	Cell
Volume	173
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2018.03.001
State	Published - Mar 22 2018

Funding

We thank Florent Allagnat for critical discussions and reading the manuscript; Andrew Thompson, Nandan Nurukar, and Rohan Kulkarni for technical assistance; Gokhan Hotamisligil for the use of the Seahorse; John Asara for assistance with metabolomics; Frederick Bowman for the use of the laser Doppler imager; and Constance Cepko for the use of the two-photon microscope. This work was supported by grants from the Swiss National Science Foundation ( P1LAP3_158895 ) to A.L.; the National Science Foundation ( NSF-DGE1144152 ) to L.E.B.; the Canadian Institutes of Health Sciences to R.W.; the NIH ( EB00262 ) to C.S.C.; the American Heart Association ( 12GRNT9510001 and 12GRNT1207025 ), the Lea Carpenter du Pont Vascular Surgery Fund , and the Carl and Ruth Shapiro Family Foundation to C.K.O.; and the NIH ( AG036712 and DK090629 ) and the Charoen Pokphand Group to J.R.M.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2018.03.001

Cite this

Longchamp, A., Mirabella, T., Arduini, A., MacArthur, M. R., Das, A., Treviño-Villarreal, J. H., Hine, C., Ben-Sahra, I., Knudsen, N. H., Brace, L. E., Reynolds, J., Mejia, P., Tao, M., Sharma, G., Wang, R., Corpataux, J. M., Haefliger, J. A., Ahn, K. H., Lee, C. H., ... Mitchell, J. R. (2018). Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H₂S Production. Cell, 173(1), 117-129.e14. https://doi.org/10.1016/j.cell.2018.03.001

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title = "Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production",

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. Restricting dietary sulfur amino acids can trigger angiogenesis and improve vascular health.",

author = "Alban Longchamp and Teodelinda Mirabella and Alessandro Arduini and MacArthur, {Michael R.} and Abhirup Das and Trevi{\~n}o-Villarreal, {J. Humberto} and Christopher Hine and Issam Ben-Sahra and Knudsen, {Nelson H.} and Brace, {Lear E.} and Justin Reynolds and Pedro Mejia and Ming Tao and Gaurav Sharma and Rui Wang and Corpataux, {Jean Marc} and Haefliger, {Jacques Antoine} and Ahn, {Kyo Han} and Lee, {Chih Hao} and Manning, {Brendan D.} and Sinclair, {David A.} and Chen, {Christopher S.} and Ozaki, {C. Keith} and Mitchell, {James R.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = mar,

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doi = "10.1016/j.cell.2018.03.001",

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Longchamp, A, Mirabella, T, Arduini, A, MacArthur, MR, Das, A, Treviño-Villarreal, JH, Hine, C, Ben-Sahra, I, Knudsen, NH, Brace, LE, Reynolds, J, Mejia, P, Tao, M, Sharma, G, Wang, R, Corpataux, JM, Haefliger, JA, Ahn, KH, Lee, CH, Manning, BD, Sinclair, DA, Chen, CS, Ozaki, CK & Mitchell, JR 2018, 'Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H₂S Production', Cell, vol. 173, no. 1, pp. 117-129.e14. https://doi.org/10.1016/j.cell.2018.03.001

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T1 - Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production

AU - Longchamp, Alban

AU - Mirabella, Teodelinda

AU - Arduini, Alessandro

AU - MacArthur, Michael R.

AU - Das, Abhirup

AU - Treviño-Villarreal, J. Humberto

AU - Hine, Christopher

AU - Ben-Sahra, Issam

AU - Knudsen, Nelson H.

AU - Brace, Lear E.

AU - Reynolds, Justin

AU - Mejia, Pedro

AU - Tao, Ming

AU - Sharma, Gaurav

AU - Wang, Rui

AU - Corpataux, Jean Marc

AU - Haefliger, Jacques Antoine

AU - Ahn, Kyo Han

AU - Lee, Chih Hao

AU - Manning, Brendan D.

AU - Sinclair, David A.

AU - Chen, Christopher S.

AU - Ozaki, C. Keith

AU - Mitchell, James R.

PY - 2018/3/22

Y1 - 2018/3/22

N2 - 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. Restricting dietary sulfur amino acids can trigger angiogenesis and improve vascular health.

AB - 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. Restricting dietary sulfur amino acids can trigger angiogenesis and improve vascular health.

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