期刊
CELL METABOLISM
卷 19, 期 2, 页码 246-258出版社
CELL PRESS
DOI: 10.1016/j.cmet.2013.12.014
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology
- Takeda Science Foundation
- Japan Vascular Disease Research Foundation
- Astra Zeneca Research Grant
- Suzuken Memorial Foundation
- AHA
- CAPES foundation
- NHLBI
- NIGMS
- ADA
- Ellison Medical Foundation
- [HL094262]
- [HL076136]
- [HL108229]
- Grants-in-Aid for Scientific Research [21117007, 25293184] Funding Source: KAKEN
Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1 alpha is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1 alpha expression is high in diabetic rodents and humans and that PGC-1 alpha powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1 alpha induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1 alpha 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-1 alpha rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1 alpha thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1 alpha contributes to multiple aspects of vascular dysfunction in diabetes.
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