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

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

journal_name

Circulation

journal_title

Circulation

authors

Wang CY,Wen MS,Wang HW,Hsieh IC,Li Y,Liu PY,Lin FC,Liao JK

doi

10.1161/CIRCULATIONAHA.108.790469

subject

Has Abstract

pub_date

2008-11-18 00:00:00

pages

2166-73

issue

21

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.108.790469

journal_volume

118

pub_type

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