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

Abstract：

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 but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle. OBJECTIVE:To test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle. METHODS AND RESULTS: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.

journal_name

Circ Res

journal_title

Circulation research

authors

Rowe GC,Raghuram S,Jang C,Nagy JA,Patten IS,Goyal A,Chan MC,Liu LX,Jiang A,Spokes KC,Beeler D,Dvorak H,Aird WC,Arany Z

doi

10.1161/CIRCRESAHA.115.303829

subject

Has Abstract

pub_date

2014-08-15 00:00:00

pages

504-17

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.115.303829

journal_volume

115

pub_type

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