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

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 ATF3/4(low) 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 ATF3/4(low) 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.

Automated summary

The study suggests that there are two populations of muscle endothelial cells characterized by differential expression of ATF3/4, with red ATF3/4(+) mECs being more angiogenic compared to white ATF3/4(low) mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism, metabolically priming red mECs for angiogenesis. Deletion of Atf4 in ECs was found to impair exercise-induced angiogenesis.