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Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells
Cell Metabolism ( IF 27.7 ) Pub Date : 2021-08-05 , DOI: 10.1016/j.cmet.2021.07.015
Zheng Fan 1 , Guillermo Turiel 1 , Raphaela Ardicoglu 2 , Moheb Ghobrial 3 , Evi Masschelein 1 , Tea Kocijan 1 , Jing Zhang 1 , Ge Tan 4 , Gillian Fitzgerald 1 , Tatiane Gorski 1 , Abdiel Alvarado-Diaz 1 , Paola Gilardoni 1 , Christopher M Adams 5 , Bart Ghesquière 6 , Katrien De Bock 1
Affiliation  

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.



中文翻译:

运动诱导的血管生成依赖于代谢引发的 ATF3/4+ 内皮细胞

运动是成年期生理性血管生成的强大驱动力,但运动引起的血管扩张的机制却知之甚少。我们探索了骨骼肌中的内皮异质性,并确定了两个以 ATF3/4 差异表达为特征的毛细血管内皮细胞 (mEC) 群。空间映射显示 ATF3/4 + mECs 富含红色氧化肌肉区域,而 ATF3/4ECs 位于白色糖酵解纤维附近。体外体内实验表明,与白色 ATF3/4低相比,红色 ATF3/4 + mEC 更具血管生成性mEC。从机制上讲,mECs 中的 ATF3/4 控制参与氨基酸摄取和代谢的基因,并在代谢上引发红色 (ATF3/4 + ) mECs 用于血管生成。因此,补充非必需氨基酸和过表达 ATF4 增加了白色 mEC 的增殖。最后,删除ECs 中的Atf4会损害运动诱导的血管生成。我们的研究结果表明,空间代谢血管多样性决定了肌肉 ECs 的血管生成潜力。

更新日期:2021-09-07
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