@article{430b2c10b2ce493583607e1ae19530d6,
title = "Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells",
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.",
keywords = "amino acid metabolism, endothelial heterogeneity, endothelial metabolism, exercise, muscle angiogenesis, single-cell RNA-seq",
author = "Zheng Fan and Guillermo Turiel and Raphaela Ardicoglu and Moheb Ghobrial and Evi Masschelein and Tea Kocijan and Jing Zhang and Ge Tan and Gillian Fitzgerald and Tatiane Gorski and Abdiel Alvarado-Diaz and Paola Gilardoni and Adams, {Christopher M.} and Bart Ghesqui{\`e}re and {De Bock}, Katrien",
note = "Funding Information: This manuscript is dedicated to James R. Mitchell (1971–2020). We thank him for his critical feedback and helpful suggestions and will remember him forever. We thank Veronique Juvin from SciArtWork (https://sciartwork.com/) for help with the graphical abstract, and the Functional Genomics Center Z{\"u}rich (FGCZ) as well as the ETH Flow Cytometry Core Facility (E-FCCF) for excellent technical support. This project was funded by a European Research Council (ERC) starting grant (716140), the Swiss National Science Foundation (SNF 310030B_182829), and grant #18C167 from the Novartis Foundation for Medical-Biological Research. A.A.-D. is supported by a PhD fellowship from the National Research and Technology Council of Mexico (CONACyT). K.D.B. is endowed by the Schulthess Foundation. Z.F. designed and performed the experiments. G. Turiel, M.G. and G. Tan performed the bioinformatics analysis. R.A. T.K. G.F. T.G. A.A.-D. J.Z. E.M. and P.G. contributed to data analysis and performing experiments. C.M.A. provided the Atf4 floxed mice and commented on the manuscript. B.G. supervised the metabolite analysis. K.D.B. conceptualized the study, supervised the experiments, acquired funding, and wrote the paper. These authors declare no competing interests. Funding Information: This manuscript is dedicated to James R. Mitchell (1971–2020). We thank him for his critical feedback and helpful suggestions and will remember him forever. We thank Veronique Juvin from SciArtWork ( https://sciartwork.com/ ) for help with the graphical abstract, and the Functional Genomics Center Z{\"u}rich (FGCZ) as well as the ETH Flow Cytometry Core Facility (E-FCCF) for excellent technical support. This project was funded by a European Research Council (ERC) starting grant ( 716140 ), the Swiss National Science Foundation (SNF 310030B_182829 ), and grant #18C167 from the Novartis Foundation for Medical-Biological Research . A.A.-D. is supported by a PhD fellowship from the National Research and Technology Council of Mexico ( CONACyT ). K.D.B. is endowed by the Schulthess Foundation. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = sep,
day = "7",
doi = "10.1016/j.cmet.2021.07.015",
language = "English (US)",
volume = "33",
pages = "1793--1807.e9",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "9",
}