| First Author | Wang CY | Year | 2008 |
| Journal | Circulation | Volume | 118 |
| Issue | 21 | Pages | 2166-73 |
| PubMed ID | 18981300 | Mgi Jnum | J:165618 |
| Mgi Id | MGI:4837819 | Doi | 10.1161/CIRCULATIONAHA.108.790469 |
| Citation | Wang CY, et al. (2008) Increased vascular senescence and impaired endothelial progenitor cell function mediated by mutation of circadian gene Per2. Circulation 118(21):2166-73 |
| abstractText | 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. |
