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Cell Metab. 2014 Feb 4;19(2):246-58. doi: 10.1016/j.cmet.2013.12.014.

Endothelial PGC-1α mediates vascular dysfunction in diabetes.

Author information

1
Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Global COE Program, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: nsawada@medicine.bsd.uchicago.edu.
2
Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
3
Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Global COE Program, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
4
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA; Instituto de Cardiologia do Rio Grande do Sul, Fundacao Universitaria de Cardiologia, Porto Alegre, Brazil.
5
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Vascular Biology Program and Department of Surgery, Children's Hospital, Boston, MA 02115, USA.
7
Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Laboratory of Molecular Nutrition, Graduate School of Environmental and Life Science, Kyoto Prefectural University, Kyoto 606-8522, Japan.
8
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
9
Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Global COE Program, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
10
Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
11
Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
12
Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
13
Department of Plastic and Reconstructive Surgery, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
14
Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Electronic address: zarany@bidmc.harvard.edu.

Abstract

Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1α in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1α rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1α thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1α contributes to multiple aspects of vascular dysfunction in diabetes.

PMID:
24506866
PMCID:
PMC4040246
DOI:
10.1016/j.cmet.2013.12.014
[Indexed for MEDLINE]
Free PMC Article
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