title: Endothelial PGC-1α mediates vascular dysfunction in diabetes.
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.
authors: 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.
authors: Naoki
authors: N
authors: Sawada
authors: Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Aihua
authors: A
authors: Jiang
authors: 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.
authors: Fumihiko
authors: F
authors: Takizawa
authors: Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Adeel
authors: A
authors: Safdar
authors: 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.
authors: Andre
authors: A
authors: Manika
authors: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Yevgenia
authors: Y
authors: Tesmenitsky
authors: Vascular Biology Program and Department of Surgery, Children's Hospital, Boston, MA 02115, USA.
authors: Kyu-Tae
authors: KT
authors: Kang
authors: Vascular Biology Program and Department of Surgery, Children's Hospital, Boston, MA 02115, USA.
authors: Joyce
authors: J
authors: Bischoff
authors: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Hermann
authors: H
authors: Kalwa
authors: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Juliano L
authors: JL
authors: Sartoretto
authors: 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.
authors: Yasutomi
authors: Y
authors: Kamei
authors: Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Laura E
authors: LE
authors: Benjamin
authors: Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors: Hirotaka
authors: H
authors: Watada
authors: 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.
authors: Yoshihiro
authors: Y
authors: Ogawa
authors: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
authors: Yasutomi
authors: Y
authors: Higashikuni
authors: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Chase W
authors: CW
authors: Kessinger
authors: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Farouc A
authors: FA
authors: Jaffer
authors: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Thomas
authors: T
authors: Michel
authors: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
authors: Masataka
authors: M
authors: Sata
authors: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Kevin
authors: K
authors: Croce
authors: Department of Plastic and Reconstructive Surgery, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors: Rica
authors: R
authors: Tanaka
authors: Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Electronic address: zarany@bidmc.harvard.edu.
authors: Zolt
authors: Z
authors: Arany
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors