Laboratory of Exercise and Health, Department Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, 8603 Zurich, Switzerland.
Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
Cell Metab. 2020 Jun 2;31(6):1136-1153.e7. doi: 10.1016/j.cmet.2020.05.004.
Endothelial cell (EC)-derived signals contribute to organ regeneration, but angiocrine metabolic communication is not described. We found that EC-specific loss of the glycolytic regulator pfkfb3 reduced ischemic hindlimb revascularization and impaired muscle regeneration. This was caused by the reduced ability of macrophages to adopt a proangiogenic and proregenerative M2-like phenotype. Mechanistically, loss of pfkfb3 reduced lactate secretion by ECs and lowered lactate levels in the ischemic muscle. Addition of lactate to pfkfb3-deficient ECs restored M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Moreover, VEGF production by lactate-polarized macrophages was increased, resulting in a positive feedback loop that further stimulated angiogenesis. Finally, increasing lactate levels during ischemia rescued macrophage polarization and improved muscle reperfusion and regeneration, whereas macrophage-specific mct1 deletion prevented M2-like polarization. In summary, ECs exploit glycolysis for angiocrine lactate shuttling to steer muscle regeneration from ischemia.
内皮细胞（EC）衍生的信号有助于器官再生，但血管生成代谢通讯尚未描述。我们发现，糖酵解调节剂 pfkfb3 的 EC 特异性缺失会减少缺血性后肢再血管化并损害肌肉再生。这是由于巨噬细胞采用促血管生成和促再生的 M2 样表型的能力降低所致。从机制上讲，pfkfb3 的缺失会减少 EC 分泌的乳酸，并降低缺血肌肉中的乳酸水平。向 pfkfb3 缺陷型 EC 添加乳酸可通过 MCT1 依赖性方式恢复 M2 样极化。EC 的乳酸穿梭使巨噬细胞能够促进肌肉祖细胞的增殖和融合。此外，乳酸极化的巨噬细胞中 VEGF 的产生增加，形成正反馈回路，进一步刺激血管生成。最后，在缺血过程中增加乳酸水平可挽救巨噬细胞极化并改善肌肉再灌注和再生，而巨噬细胞特异性 mct1 缺失可防止 M2 样极化。总之，EC 利用糖酵解进行血管生成的乳酸穿梭，从而从缺血中引导肌肉再生。
