TY - JOUR
T1 - Endothelial PGC-1α mediates vascular dysfunction in diabetes
AU - Sawada, Naoki
AU - Jiang, Aihua
AU - Takizawa, Fumihiko
AU - Safdar, Adeel
AU - Manika, Andre
AU - Tesmenitsky, Yevgenia
AU - Kang, Kyu Tae
AU - Bischoff, Joyce
AU - Kalwa, Hermann
AU - Sartoretto, Juliano L.
AU - Kamei, Yasutomi
AU - Benjamin, Laura E.
AU - Watada, Hirotaka
AU - Ogawa, Yoshihiro
AU - Higashikuni, Yasutomi
AU - Kessinger, Chase W.
AU - Jaffer, Farouc A.
AU - Michel, Thomas
AU - Sata, Masataka
AU - Croce, Kevin
AU - Tanaka, Rica
AU - Arany, Zolt
N1 - Funding Information:
N.S. was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology; the Takeda Science Foundation; the Japan Vascular Disease Research Foundation; the Astra Zeneca Research Grant; and the Suzuken Memorial Foundation. H.K. and A.J. were supported by postdoctoral fellowships from the AHA. J.B. was supported by HL094262. A.M. was supported by the CAPES foundation. C.W.K. was supported by HL076136. F.A.J. was supported by HL108229. T.M. was supported by grants from the NHLBI and NIGMS, and Z.A. was supported by the ADA, the Ellison Medical Foundation, and the NHLBI.
PY - 2014/2/4
Y1 - 2014/2/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2013.12.014
DO - 10.1016/j.cmet.2013.12.014
M3 - Article
C2 - 24506866
AN - SCOPUS:84893480253
SN - 1550-4131
VL - 19
SP - 246
EP - 258
JO - Cell metabolism
JF - Cell metabolism
IS - 2
ER -
