Skeletal myofiber VEGF is required for the exercise training-induced increase in dentate gyrus neuronal precursor cells
Skeletal myofiber VEGF is required for the exercise training-induced increase in dentate gyrus neuronal precursor cells
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发表时间：
2018
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通讯作者：
Benjamin Rich;Miriam Scadeng;P. Wagner;E. Breen
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作者：
Benjamin Rich;Miriam Scadeng;P. Wagner;E. Breen
运动是海马齿状回神经发生的信号。这种现象需要血管内皮生长因子(VEGF)来源于血脑屏障外，但尚未确定细胞来源。因此，我们推测骨骼肌纤维产生的血管内皮生长因子在运动训练后调节海马神经元前体细胞的增殖中起作用。这在成年条件骨骼肌纤维特异的VEGF基因消融小鼠(VEGFHSA-/-)上进行了测试，给VEGFHSA-/-和未消融(VEGFf/f)的小鼠提供了14天的跑轮。训练结束后，用功能磁共振成像(FMRI)检测大鼠海马区脑血流量(CBF)，免疫荧光法检测神经元前体细胞(BrDU+/Nestin+)。在急性跑台跑步试验中，血管内皮生长因子f/f训练组在速度和耐力方面均有改善(p<；0.05)。而血管内皮生长因子HSA-/-组则无此作用。在VEGFf/f(p<；0.05)中，随着训练的进行，增殖的神经元前体细胞的数量增加，但在VEGFHSA-/-小鼠中没有增加。运动训练或骨骼肌纤维血管内皮细胞生长因子基因缺失对该区域内皮细胞(CD31+)数量无明显影响。然而，在未训练和训练的VEGFHSA-/-小鼠中，通过海马区的静息血流低于未训练的VEGFf/f小鼠(p<；0.05)。急性低氧刺激降低了未训练的VEGFf/f、未训练的VEGFHSA-/-和训练的VEGFHSA-/-小鼠的脑血流量(p<；0.05)，但训练的VEGFf/f小鼠没有。VEGFf/f小鼠，而不是VEGFHSA-/-小鼠，能够在跑步机上以足以增加海马体VEGF值的强度快速跑步。这些数据表明，骨骼肌纤维表达的血管内皮生长因子可能直接或间接地调节海马区的血流和神经发生。4.通过诱导肌肉纤维中的血管内皮生长因子基因敲除而使海马区的血管内皮生长因子水平静息；5.一次急性运动增加了血管内皮生长因子f/f小鼠的海马区血管内皮生长因子水平，但增加了血管内皮生长因子HSA-/-小鼠的水平；6.低氧激发10%的氧气可降低训练和未训练的血管内皮生长因子HSA-/-小鼠和正常氧训练的血管内皮生长因子f/f小鼠的脑血流量。
Exercise signals neurogenesis in the dentate gyrus of the hippocampus. This phenomenon requires vascular endothelial growth factor (VEGF) originating from outside the blood brain barrier, but no cellular source has been identified. Thus, we hypothesized that VEGF produced by skeletal myofibers plays a role in regulating hippocampal neuronal precursor cell proliferation following exercise training. This was tested in adult conditional skeletal myofiber-specific VEGF gene-ablated mice (VEGF HSA-/- ) by providing VEGF HSA-/- and non-ablated (VEGF f/f ) littermates with running wheels for 14 days. Following this training period, hippocampal cerebral blood flow (CBF) was measured by functional magnetic resonance imaging (fMRI) and neuronal precursor cells (BrDU+/Nestin+) were detected by immunofluorescence. The VEGF f/f trained group showed improvements in both speed and endurance capacity in acute treadmill running tests (p<0.05). The VEGF HSA-/- group did not. The number of proliferating neuronal precursor cells was increased with training in VEGF f/f (p<0.05) but not in VEGF HSA-/-mice. Endothelial cell (CD31+) number did not change in this region with exercise training or skeletal myofiber VEGF gene deletion. However, resting blood flow through the hippocampal region was lower in VEGF HSA-/- mice, both untrained and trained, than untrained VEGF f/f mice (p<0.05). An acute hypoxic challenge decreased CBF (p<0.05) in untrained VEGF f/f , untrained VEGF HSA-/- , and trained VEGF HSA-/- , but not trained VEGF f/f mice. VEGF f/f , but not VEGF HSA-/- mice, were able to acutely run on a treadmill at an intensity sufficient to increase hippocampus VEGF levels. These data suggest that VEGF expressed by skeletal myofibers may directly or indirectly regulate both hippocampal blood flow and neurogenesis. a in of on 4. Resting VEGF levels in the hippocampus by induced VEGF knockout in myofibers; 5. A bout of acute exercise increases hippocampal VEGF levels in VEGF f/f mice, but VEGF HSA-/- mice; 6. A hypoxic challenge with 10% inspired O 2 lowers cerebral blood flow in trained and untrained VEGF HSA-/- mice and trained VEGF f/f mice from normoxia.