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

Abstract

Summary 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.

Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

“…TFs in common between old heterochronic and young unpaired ECs that reflect the RJV construct included essential regulators of EC function such as Tbx3 71,72 , Foxo4 73 which is a member of the FOXO family of TFs that are components of a fundamental aging regulatory pathway, Patz1 , which has been implicated in regulating p53 levels and senescence in ECs 74 , and Arnt , which participates in aryl hydrocarbon receptor signaling and is involved in several aspects of vascular biology 75 (Fig 6d). Likewise, young heterochronic and old unpaired ECs that reflect the AGA construct shared the hypoxia response genes Atf1, Atf2 , and Hif1a , indicating a stressed EC profile, as well as Atf4 which has been involved in angiogenesis 76 (Fig 6e).…”

Resistance exercise enhances long-term mTORC1 sensitivity to leucine

“…Previous work in other cell types has shown that the activating transcription factor 4 (ATF4) plays a key role in maintaining intracellular amino acid levels through regulating the expression of a variety of genes involved in amino acid uptake, sensing and metabolism [ [47] , [48] , [49] ]. We thus went on to investigate whether ATF4 was increased by exercise.…”

“…Finally, we previously observed that in muscle endothelial cells, endothelial ATF4 is required for the increased vascular density upon exercise training [ 48 ]. Together with our current observations, we speculate that ATF4 might be a crucial anabolic effector that allows cell growth (whether muscle growth or endothelial growth for proliferation) following exercise.…”

Exercise Modifies the Transcriptional Regulatory Features of Monocytes in Alzheimer’s Patients: A Multi-Omics Integration Analysis Based on Single Cell Technology

“…Treadmill exercise can promote sciatic nerve injury regeneration through ATF3 upregulation ( Kim et al, 2020 ). In contrast, silencing of the ATF3 family gene can inhibit exercise-induced angiogenesis ( Fan et al, 2021 ). ATF3 can also promote the progression of neurodegenerative diseases ( Bao et al, 2021 ).…”