[PDF][PDF] Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization
Cell metabolism, 2020•cell.com
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 …
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 …
Summary
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.
cell.com