Increased vascular senescence and impaired endothelial progenitor cell function mediated by mutation of circadian gene Per2.
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.
Wang
Chao-Yung
CY
Brigham and Women's Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139, USA.
Wen
Ming-Shien
MS
Wang
Hong-Wei
HW
Hsieh
I-Chang
IC
Li
Yuxin
Y
Liu
Ping-Yen
PY
Lin
Fun-Chung
FC
Liao
James K
JK
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*
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt