PGC-1α induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle

PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.

To test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle.

Here, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease. Conclusions: PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.