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

Journal: Cell metabolism 2022;33(9):1793-1807.e9

PMID: 34358431

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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 ATF3/4 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 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.

Address: Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich 8603, Switzerland.; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich 8603, Switzerland; Laboratory of Molecular and Behavioral Neuroscience, Department of Health Sciences and Technology, ETH Zürich, Zürich 8057, Switzerland.; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich 8603, Switzerland; Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON M5T 2S8, Canada.; Functional Genomics Center Zürich, ETH/University of Zürich, Zürich 8093, Switzerland.; Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, USA.; Metabolomics Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, Cancer Institute, KU Leuven, Leuven, Belgium.; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich 8603, Switzerland. Electronic address: [email protected].

DOI: 10.1016/j.cmet.2021.07.015

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MeSH Terms: Activating Transcription Factor 3, Adult, Endothelial Cells, Humans, Muscle Fibers, Skeletal, Muscle, Skeletal, Neovascularization, Pathologic, Neovascularization, Physiologic