Exercise training stimulates ischemia-induced neovascularization via phosphatidylinositol 3-kinase/Akt-dependent hypoxia-induced factor-1 alpha reactivation in mice of advanced age.
Exercise training stimulates ischemia-induced neovascularization via phosphatidylinositol 3-kinase/Akt-dependent hypoxia-induced factor-1 alpha reactivation in mice of advanced age.
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DOI：
10.1161/circulationaha.109.909218
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发表时间：
2010-08-17
期刊：
影响因子：
37.8
通讯作者：
Murohara T
中科院分区：
文献类型：
--
作者：
Cheng XW;Kuzuya M;Kim W;Song H;Hu L;Inoue A;Nakamura K;Di Q;Sasaki T;Tsuzuki M;Shi GP;Okumura K;Murohara T
运动在包括缺血在内的病理状况下刺激血管反应；然而，运动改善与衰老相关的缺氧诱导因子（HIF）-1α介导的对缺氧的受损反应的分子机制知之甚少。在此，我们报道游泳训练（ST）调节老年（24月龄）小鼠对缺血的血管反应。
从手术后第1天开始维持游泳训练（每天游泳1小时）的老年野生型小鼠（MMP - 2 +/+）被随机分为4组，分别用溶媒、LY294002或去铁胺处理14天。处于久坐状态的小鼠作为对照。在MMP - 2 +/+小鼠中，ST增加了血流量、毛细血管密度以及p - Akt、HIF - 1α、血管内皮生长因子、Fit - 1和基质金属蛋白酶 - 2（MMP - 2）的水平。ST还增加了循环内皮祖细胞的数量及其与HIF - 1α激活相关的功能。所有这些作用被磷脂酰肌醇3 - 激酶抑制剂LY294002减弱，被HIF - 1α稳定剂去铁胺增强，并因MMP - 2基因敲除而受损。最后，骨髓移植证实ST增强了老年小鼠内皮祖细胞向缺血部位的归巢。
在老年阶段，ST可通过磷脂酰肌醇3 - 激酶依赖的机制改善对缺氧的新生血管形成，该机制由HIF - 1α/血管内皮生长因子/MMP - 2通路介导。
Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1α–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. 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-1α, 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-1α. All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1α 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. ST can improve neovascularization in response to hypoxia via a phosphatidylinositol 3-kinase–dependent mechanism that is mediated by the HIF-1α/vascular endothelial growth factor/MMP-2 pathway in advanced age.