Endothelial Cells Control Muscle Regeneration Through Angiocrine Lactate

Endothelial cell (EC) derived angiocrine 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. Adding lactate to conditioned medium from pfkfb3-deficient ECs rescued M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Macrophages also secreted more VEGF, thereby creating a positive feedback loop that further stimulates angiogenesis. Finally, increasing lactate levels during ischemia sufficed to rescue macrophage polarization, resulting in improved muscle reperfusion and regeneration. In summary, ECs exploit their glycolytic capacity for angiocrine lactate shuttling to steer muscle regeneration from ischemia.