title: 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.
  
  
  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.
authors.affiliation: Brigham and Women's Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139, USA.
authors.forename: Chao-Yung
authors.initials: CY
authors.lastname: Wang
authors.forename: Ming-Shien
authors.initials: MS
authors.lastname: Wen
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: I-Chang
authors.initials: IC
authors.lastname: Hsieh
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.forename: Ping-Yen
authors.initials: PY
authors.lastname: Liu
authors.forename: Fun-Chung
authors.initials: FC
authors.lastname: Lin
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000235:genetics; D016026:Bone Marrow Transplantation; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D019650:Hematopoietic Stem Cell Mobilization; D006439:Hemodynamics / Q000235:genetics; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt