ArticleCell2018
Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H
Registry-linked trialOpen access · bronzeAbstract read
In one paragraph
Article in Cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05457881 (Short-Term Endogenous Hydrogen Sulfide Upregulation For Vein Graft Disease), which is not on this map. Cited by 191 papers.
0numbers the graph read from it
0cells of the map it votes in
191citing papers in PubMed
19.1field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Short-Term Endogenous Hydrogen Sulfide Upregulation For Vein Graft Disease
Who cites it
191 citing papers in PubMed, 324 citations in OpenAlex.
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- Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
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- Eight-week dietary methionine restriction does not impair resistance exercise-induced mTORC1 signalling activation in rats.Biochemistry and biophysics reports · 2026Article
- Glucose deprivation drives LIF-dependent lung cancer.Nature metabolism · 2026Article
- Molecular mechanisms underlying the lifespan and healthspan benefits of dietary restriction across species.Frontiers in genetics · 2026Review
- Exercise benefits in metabolism on cardiovascular disease.Frontiers in cardiovascular medicine · 2026Review
- Metabolic alterations and redox homeostasis in ferroptosis: emerging mechanisms and therapeutic implications.Archives of medical science : AMS · 2026Article
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- Transsulfuration metabolism is essential for ferroptosis resistance in quiescent endothelial cells.Cell death & disease · 2025Article
- Article
131 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on byH2018
Authors and funding
24 authors at 8 institutions in 5 countries.
Alban LongchampDepartment 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.
Teodelinda MirabellaTissue Microfabrication Lab, Department of Biomedical Engineering, Boston University, Boston, MA, USA; Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
Alessandro ArduiniDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Michael R MacArthurDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Abhirup DasGlenn 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.
J Humberto Treviño-VillarrealDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Christopher HineDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Issam Ben-SahraDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Nelson H KnudsenDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Lear E BraceDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Justin ReynoldsDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Pedro MejiaDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Ming TaoDepartment of Surgery and the Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
Gaurav SharmaDepartment of Surgery and the Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
Rui WangCardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON, Canada.
Jean-Marc CorpatauxDepartment of Vascular Surgery, Laboratory of Experimental Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Jacques-Antoine HaefligerDepartment of Vascular Surgery, Laboratory of Experimental Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Kyo Han AhnDepartment of Chemistry, Postech, 77 Cheongam-Ro, Nam-Gu, Pohang, 37673, Republic of Korea.
Chih-Hao LeeDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Brendan D ManningDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
David A SinclairGlenn 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.
Christopher S ChenTissue Microfabrication Lab, Department of Biomedical Engineering, Boston University, Boston, MA, USA; Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA.
C Keith OzakiDepartment of Surgery and the Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
James R MitchellDepartment of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: jmitchel@hsph.harvard.edu.
Harvard University · USBrigham and Women's Hospital · USBoston University · USUniversity Hospital of Lausanne · CHCenter for Human Genetics · USLaurentian University · CAPohang University of Science and Technology · KRUNSW Sydney · AU
Funding
Decoding and Targeting the PI3K-mTOR Signaling Network in CancerR35CA197459 · NCI · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · PI BRENDAN D. MANNING · 2015 to 2026
$10.8MREGULATION OF ANGIOGENESIS BY MICROENVIRONMENTAL CUESR01EB000262 · NIBIB · UNIVERSITY OF PENNSYLVANIA · PI CHEN, CHRISTOPHER S · 2002 to 2023
$6.2MUncovering the Human SecretomeDP1AG058605 · NIA · HARVARD MEDICAL SCHOOL · PI SINCLAIR, DAVID A. · 2017 to 2021
$5.9MRole of Sgs1 DNA helicase in telomere maintenanceR01AG019719 · NIA · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI SINCLAIR, DAVID A. · 2001 to 2022
$5.3MSIRT1 as a regulator of health and lifespan of mammalsR37AG028730 · NIA · HARVARD MEDICAL SCHOOL · PI SINCLAIR, DAVID A. · 2012 to 2021
$4.1MMechanisms of dietary control of the transsulfuration pathway and increased endogenous hydrogen sulfide productionR01DK090629 · NIDDK · HARVARD SCHOOL OF PUBLIC HEALTH · PI MITCHELL, SARAH JAYNE · 2011 to 2019
$3.0MElucidating mechanisms of SIRT1 activationR01DK100263 · NIDDK · HARVARD MEDICAL SCHOOL · PI SINCLAIR, DAVID A. · 2016 to 2020
$2.5MSIRT as a regulator of health and lifespan of mammalsR01AG028730 · NIA · HARVARD MEDICAL SCHOOL · PI SINCLAIR, DAVID A. · 2007 to 2011
$1.7MProtection against renal ischemic injury by short term dietary restrictionR01AG036712 · NIA · HARVARD SCHOOL OF PUBLIC HEALTH · PI MITCHELL, JAMES R. · 2010 to 2014
$1.6MDietary restriction promotes vascular health through hydrogen sulfide-mediated angiogenesisR56AG036712 · NIA · HARVARD SCHOOL OF PUBLIC HEALTH · PI MITCHELL, JAMES R. · 2017 to 2017
$398kCIHRNCI NIH HHS R35 CA197459NIA NIH HHS DP1 AG058605NIA NIH HHS R01 AG019719NIA NIH HHS R01 AG028730NIA NIH HHS R01 AG036712NIA NIH HHS R37 AG028730NIA NIH HHS R56 AG036712NIBIB NIH HHS R01 EB000262NIDDK NIH HHS R01 DK090629NIDDK NIH HHS R01 DK100263
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 (H
Indexed as
Activating Transcription Factor 4Amino Acids, SulfurAnimalsCystathionine gamma-LyaseDisease Models, AnimalFemaleHumansHuman Umbilical Vein Endothelial CellsHydrogen SulfideHypoxia-Inducible Factor 1, alpha SubunitIschemiaMaleMiceMice, Inbred C57BLNeovascularization, PhysiologicPhysical Conditioning, AnimalActivating Transcription Factor 4Amino Acids, SulfurCystathionine gamma-LyaseEif2ak4 protein, mouseHydrogen SulfideHypoxia-Inducible Factor 1, alpha SubunitProtein Serine-Threonine KinasesRNA, Small InterferingVascular Endothelial Growth Factor A
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Registered trials
NCT05457881ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.