Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Endocrinology & Metabolism, AMINO-ACID-METABOLISM, SKELETAL-MUSCLE, STRESS-RESPONSE, ADAPTIVE-RESPONSE, INSULIN, ATF4, EXPRESSION, GLUCOSE, PROLIFERATION, GLUTAMINE, amino acid metabolism, endothelial heterogeneity, endothelial metabolism, exercise, muscle angiogenesis, single-cell RNA-seq, Activating Transcription Factor 3, Adult, Endothelial Cells, Humans, Muscle Fibers, Skeletal, Muscle, Skeletal, Neovascularization, Pathologic, Neovascularization, Physiologic, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics

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.