Exercise training stimulates ischemia-induced neovascularization via phosphatidylinositol 3-kinase/Akt-dependent hypoxia-induced factor-1 alpha reactivation in mice of advanced age.
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.
Cheng
Xian Wu
XW
Department of Cardiovascular Research Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. chengxw0908@yahoo.com.cn
Kuzuya
Masafumi
M
Kim
Weon
W
Song
Haizhen
H
Hu
Lina
L
Inoue
Aiko
A
Nakamura
Kae
K
Di
Qun
Q
Sasaki
Takeshi
T
Tsuzuki
Michitaka
M
Shi
Guo-Ping
GP
Okumura
Kenji
K
Murohara
Toyoaki
T
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*
D004793:Enzyme Reactivators; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt