Increased vascular senescence and impaired endothelial progenitor cell function mediated by mutation of circadian gene Per2

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

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)

Abstract

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 (Per2m/m) mice is mediated in part by increased vascular senescence and impaired endothelial progenitor cell (EPC) function. Methods and Results - Endothelial cells from Per2m/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 Per2m/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 Per2m/m mice. However, compared with wild-type bone marrow transplantation mice, EPC mobilization was impaired in Per2m/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 Per2m/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.

Original languageEnglish
Pages (from-to)2166-2173
Number of pages8
JournalCirculation
Volume118
Issue number21
DOIs
Publication statusPublished - 2008 Nov 18

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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