Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells

Zheng Fan, Guillermo Turiel, Raphaela Ardicoglu, Moheb Ghobrial, Evi Masschelein, Tea Kocijan, Jing Zhang, Ge Tan, Gillian Fitzgerald, Tatiane Gorski, Abdiel Alvarado-Diaz, Paola Gilardoni, Christopher M. Adams, Bart Ghesquière, Katrien De Bock

Research output: Contribution to journalArticlepeer-review


Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cell (mEC) populations that are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4+ mECs are enriched in red oxidative muscle areas while ATF3/4low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4+ mECs are more angiogenic when compared with white ATF3/4low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4+) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.

Original languageEnglish (US)
Pages (from-to)1793-1807.e9
JournalCell Metabolism
Issue number9
StatePublished - Sep 7 2021


  • amino acid metabolism
  • endothelial heterogeneity
  • endothelial metabolism
  • exercise
  • muscle angiogenesis
  • single-cell RNA-seq

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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