Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells
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Date
2021-09-07
Publication Type
Journal Article
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yes
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Abstract
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.
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published
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Journal / series
Volume
33 (9)
Pages / Article No.
1793 - 1807000000000
Publisher
Cell Press
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Subject
single-cell RNA-Seq; exercise; endothelial metabolism; endothelial heterogeneity; amino acid metabolism; muscle angiogenesis
Organisational unit
09560 - De Bock, Katrien / De Bock, Katrien
02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
Notes
Funding
716140 - Understanding the metabolic cross-talk between the muscle and the endothelium: implications for exercise training and insulin sensitivity (EC)
176056 - Understanding Exercise-Induced Endothelial Metabolic Reprogramming To Promote Ischemic Revascularization (SNF)
176056 - Understanding Exercise-Induced Endothelial Metabolic Reprogramming To Promote Ischemic Revascularization (SNF)