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PNAS 106 (50): 21401-21406

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / PHYSIOLOGY

The transcriptional coactivator PGC-1{alpha} mediates exercise-induced angiogenesis in skeletal muscle

Jessica Chinsomboona, Jorge Ruasb, Rana K. Guptab, Robyn Thoma, Jonathan Shoaga, Glenn C. Rowea, Naoki Sawadaa,c, Srilatha Raghurama, and Zoltan Aranya,1

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.

Abstract: Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPAR{gamma} coactivator (PGC)-1{alpha} is a potent transcriptional co-activator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1{alpha} mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1{alpha} in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1{alpha} from an alternate promoter. The induction of PGC-1{alpha} depended on β-adrenergic signaling. β-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1{alpha}. The orphan nuclear receptor ERR{alpha} mediated the induction of VEGF by PGC-1{alpha}, and mice lacking ERR{alpha} also failed to increase vascular density after exercise. These data demonstrate that β-adrenergic stimulation of a PGC-1{alpha}/ERR{alpha}/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.

Key Words: VEGF • ERR{alpha} • 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; and Z.A. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0909131106/DCSupplemental.

1To whom correspondence should be addressed. E-mail: zarany{at}bidmc.harvard.edu

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