PGC-1α Induces SPP1 to Activate Macrophages and Orchestrate Functional Angiogenesis in Skeletal Muscle
Rationale: Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and Peripheral Artery Disease (PAD), but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and diabetic patients. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. PGC-1α, a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle.
Objective: To test if, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle.
Methods and Results: We show here 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, non-leaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of VEGF alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 (SPP1), and the recruitment of macrophages. SPP1 stimulates macrophages to secrete monocyte chemoattractant protein-1 (MCP-1), which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in SPP1 -/- 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 hind-limb ischemia model of PAD.
Conclusions: PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.
- skeletal muscle
- peripheral artery disease
- gene regulation
- gene therapy
- growth factors and cytokines
- Received February 27, 2014.
- Revision received June 28, 2014.
- Accepted July 9, 2014.