Endothelial PGC-1α mediates vascular dysfunction in diabetes.
Τίτλος | Endothelial PGC-1α mediates vascular dysfunction in diabetes. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Sawada, N., Jiang A., Takizawa F., Safdar A., Manika A., Tesmenitsky Y., Kang K-T., Bischoff J., Kalwa H., Sartoretto J. L., Kamei Y., Benjamin L. E., Watada H., Ogawa Y., Higashikuni Y., Kessinger C. W., Jaffer F. A., Michel T., Sata M., Croce K., Tanaka R., & Arany Z. |
Journal | Cell Metab |
Volume | 19 |
Issue | 2 |
Pagination | 246-58 |
Date Published | 2014 Feb 4 |
ISSN | 1932-7420 |
Λέξεις κλειδιά | Animals, Cell Movement, Cells, Cultured, Diabetes Mellitus, Endothelial Cells, Gene Expression Regulation, Hindlimb, Humans, Mice, Mice, Knockout, Transcription Factors |
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. |
DOI | 10.1016/j.cmet.2013.12.014 |
Alternate Journal | Cell Metab. |
PubMed ID | 24506866 |
PubMed Central ID | PMC4040246 |
Grant List | HL076136 / HL / NHLBI NIH HHS / United States HL094262 / HL / NHLBI NIH HHS / United States HL108229 / HL / NHLBI NIH HHS / United States R01 HL094262 / HL / NHLBI NIH HHS / United States R01 HL094499 / HL / NHLBI NIH HHS / United States R01 HL108229 / HL / NHLBI NIH HHS / United States |