Xian Wu Cheng, MD, PhD; Masafumi Kuzuya, MD, PhD; Weon Kim, MD, PhD; Haizhen Song, MD; Lina Hu, MD; Aiko Inoue, MS; Kae Nakamura, PhD; Qun Di, MD; Takeshi Sasaki, PhD; Michitaka Tsuzuki, MD, PhD; Guo-Ping Shi, DSc; Kenji Okumura, MD, PhD; Toyoaki Murohara, MD, PhD
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 –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.
Methods and 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 , 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 . All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1 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 /vascular endothelial
growth factor/MMP-2 pathway in advanced age.