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Circulation. 2008 Nov 18;118(21):2166-73. doi: 10.1161/CIRCULATIONAHA.108.790469. Epub 2008 Nov 3.

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

Author information

1
Brigham and Women's Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139, USA.

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.

PMID:
18981300
PMCID:
PMC2656770
DOI:
10.1161/CIRCULATIONAHA.108.790469
[Indexed for MEDLINE]
Free PMC Article

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