Published Online
on November 3, 2008

A more recent version of this article appeared on November 18, 2008

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Submitted on May 5, 2008
Accepted on September 16, 2008

Increased Vascular Senescence and Impaired Endothelial Progenitor Cell Function Mediated by Mutation of Circadian Gene Per2

Chao-Yung Wang MD, Ming-Shien Wen MD, Hong-Wei Wang MD, PhD, I-Chang Hsieh MD, Yuxin Li MD, PhD, Ping-Yen Liu MD, PhD, Fun-Chung Lin MD, and James K. Liao MD^*

From the Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Mass (C.-Y.W., H.-W.W., Y.L., P.-Y.L., J.K.L.), and Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan (C.-Y.W., M.-S.W., I.-C.H., F.-C.L.).

^* To whom correspondence should be addressed. E-mail: jliao{at}rics.bwh.harvard.edu.

Background—Alteration of the circadian rhythm and increased vascular senescence are linked to cardiovascular disease. Per2, a circadian gene, is known to regulate endothelium-dependent vasomotion. However, the mechanism by which Per2 affects endothelial function is unknown. We hypothesize that endothelial dysfunction in Per2 mutant (Per2^m/m) mice is mediated in part by increased vascular senescence and impaired endothelial progenitor cell (EPC) function.

Methods and Results—Endothelial cells from Per2^m/m mice exhibit increased protein kinase Akt signaling, greater senescence, and impaired vascular network formation and proliferation. Indeed, Per2^m/m mice have impaired blood flow recovery and developed autoamputation of the distal limb when subjected to hind-limb ischemia. Furthermore, matrigel implantation into Per2^m/m mice resulted in less neovascularization. Because EPCs contribute to angiogenesis, we studied the role of Per2 in these cells using bone marrow transplantation. Basal EPC levels were similar between wild-type and Per2^m/m mice. However, compared with wild-type bone marrow transplantation mice, EPC mobilization was impaired in Per2^m/m bone marrow transplantation mice in response to ischemia or VEGF stimulation. Bone marrow transplantation or infusion of wild-type EPC restored blood flow recovery and prevented autoamputation in Per2^m/m mice.

Conclusion—These findings indicate that mutation of Per2 causes Akt-dependent senescence and impairs ischemia-induced revascularization through the alteration of EPC function.

Key words: angiogenesis • circadian rhythm • endothelium • ischemia • senescence

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Clinical Summaries
Circulation 2008 118: 2115-2116. [Extract] [Full Text]

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