The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle.
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. PPARgamma coactivator (PGC)-1alpha is a potent transcriptional co-activator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1alpha mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1alpha in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1alpha from an alternate promoter. The induction of PGC-1alpha depended on beta-adrenergic signaling. beta-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1alpha. The orphan nuclear receptor ERRalpha mediated the induction of VEGF by PGC-1alpha, and mice lacking ERRalpha also failed to increase vascular density after exercise. These data demonstrate that beta-adrenergic stimulation of a PGC-1alpha/ERRalpha/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.
Chinsomboon
Jessica
J
Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Ruas
Jorge
J
Gupta
Rana K
RK
Thom
Robyn
R
Shoag
Jonathan
J
Rowe
Glenn C
GC
Sawada
Naoki
N
Raghuram
Srilatha
S
Arany
Zoltan
Z
D042501:Angiogenic Proteins / Q000235:genetics; D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D016491:Peripheral Vascular Diseases / Q000517:prevention & control; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation
D042501:Angiogenic Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011943:Receptors, Adrenergic, beta; D015534:Trans-Activators; D014157:Transcription Factors