title: Exercise training stimulates ischemia-induced neovascularization via phosphatidylinositol 3-kinase/Akt-dependent hypoxia-induced factor-1 alpha reactivation in mice of advanced age.
abstract: BACKGROUND
  Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1 alpha-mediated response to hypoxia associated with aging are poorly understood. Here, we report that swimming training (ST) modulates the vascular response to ischemia in aged (24-month-old) mice.
  
  
  RESULTS
  Aged wild-type mice (MMP-2(+/+)) that maintained ST (swimming 1 h/d) from day 1 after surgery were randomly assigned to 4 groups that were treated with either vehicle, LY294002, or deferoxamine for 14 days. Mice that were maintained in a sedentary condition served as controls. ST increased blood flow, capillary density, and levels of p-Akt, HIF-1 alpha, vascular endothelial growth factor, Fit-1, and matrix metalloproteinase-2 (MMP-2) in MMP-2(+/+) mice. ST also increased the numbers of circulating endothelial progenitor cells and their function associated with activation of HIF-1 alpha. All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1 alpha stabilizer; and impaired by knockout of MMP-2. Finally, bone marrow transplantation confirmed that ST enhanced endothelial progenitor cell homing to ischemic sites in aged mice.
  
  
  CONCLUSIONS
  ST can improve neovascularization in response to hypoxia via a phosphatidylinositol 3-kinase-dependent mechanism that is mediated by the HIF-1 alpha/vascular endothelial growth factor/MMP-2 pathway in advanced age.
authors.affiliation: Department of Cardiovascular Research Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. chengxw0908@yahoo.com.cn
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
authors.forename: Weon
authors.initials: W
authors.lastname: Kim
authors.forename: Haizhen
authors.initials: H
authors.lastname: Song
authors.forename: Lina
authors.initials: L
authors.lastname: Hu
authors.forename: Aiko
authors.initials: A
authors.lastname: Inoue
authors.forename: Kae
authors.initials: K
authors.lastname: Nakamura
authors.forename: Qun
authors.initials: Q
authors.lastname: Di
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Michitaka
authors.initials: M
authors.lastname: Tsuzuki
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D004793:Enzyme Reactivators / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*
chemical_list: D004793:Enzyme Reactivators; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt