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The transcriptional coactivator PGC-1 mediates exercise-induced angiogenesis in skeletal muscle
Rana K. Guptab,
Glenn C. Rowea,
Srilatha Raghurama, and
aCardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215; bDana Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115; and cGlobal Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Edited by Bruce M. Spiegelman, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA 02115, and approved October 22, 2009
Received for publication August 11, 2009.
Peripheral arterial disease (PAD) affects 5 million people inthe US and is the primary cause of limb amputations. Exerciseremains the single best intervention for PAD, in part thoughtto be mediated by increases in capillary density. How exercisetriggers angiogenesis is not known. PPAR coactivator (PGC)-1 is a potent transcriptional co-activator that regulates oxidativemetabolism in a variety of tissues. We show here that PGC-1mediates exercise-induced angiogenesis. Voluntary exercise inducedrobust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1 in skeletal muscle failed to increase capillary density inresponse to exercise. Exercise strongly induced expression ofPGC-1 from an alternate promoter. The induction of PGC-1 dependedon β-adrenergic signaling. β-adrenergic stimulationalso induced a broad program of angiogenic factors, includingvascular endothelial growth factor (VEGF). This induction requiredPGC-1. The orphan nuclear receptor ERR mediated the inductionof VEGF by PGC-1, and mice lacking ERR also failed to increasevascular density after exercise. These data demonstrate thatβ-adrenergic stimulation of a PGC-1/ERR/VEGF axis mediatesexercise-induced angiogenesis in skeletal muscle.
Key Words: VEGF ERR β-adrenergic
Author contributions: J.C. and Z.A. designed research; J.C.,J.R., J.S., G.C.R., N.S., S.R., and Z.A. performed research;J.R. and R.K.G. contributed new reagents/analytic tools; J.C.,R.T., J.S., G.C.R., N.S., S.R., and Z.A. analyzed data; andZ.A. wrote the paper.