Whitaker Vivian R, Cui Lin, Miller Scott, Yu Shan P, Wei Ling
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Cereb Blood Flow Metab. 2007 Jan;27(1):57-68. doi: 10.1038/sj.jcbfm.9600318. Epub 2006 May 3.
Post-ischemia angiogenesis and vascular plasticity help to restore blood flow to ischemic tissue and likely benefit long-term functional recovery. Physical activity has been shown to cause morphologic and functional effects, including promoting angiogenesis in normal or injured animals. A therapeutic effect of peripheral activity on central angiogenesis after cerebral ischemia, however, has not been studied. In the present study of whisker-barrel cortex ischemia in the mouse model, we tested the hypothesis that enhancing whisker activity and sensory input to the ischemic barrel cortex might promote post-ischemia cerebral angiogenesis. Three days after focal ischemia in adult mice, the whiskers corresponding to the ischemic barrel cortex were stimulated by two methods: (1) whiskers on the right side of the mouse face were trimmed away, so the left whiskers were overused by the animals, (2) left whiskers were manually stimulated to enhance input signals to the ischemic barrel cortex. Western blot analysis showed that whisker stimulation increased expression of the angiogenic factors vascular endothelial growth factor, basic fibroblast growth factor, Tie-1, angiopoietin-2 (Ang-2), and possibly Ang-1. Co-immunostaining with markers for proliferation (5-bromo-2'-deoxyuridine (BrdU)) and vascular endothelial cells (Glut-1/CD-31) identified vessel proliferation in the penumbra region. Whisker stimulation increased BrdU-positive endothelial cells and vessels in this region 7 and 14 days after ischemia. Whisker stimulation also attenuated endothelial cell death and increased local cerebral blood flow. Our data suggest that appropriately enhanced peripheral activity and afferent signals to the ischemic cortex can promote post-ischemic angiogenesis, which may imply beneficial effects of specific physical therapy on long-term recovery from ischemic stroke.
缺血后血管生成和血管可塑性有助于恢复缺血组织的血流，并可能有益于长期功能恢复。体育活动已被证明会产生形态学和功能上的影响，包括促进正常或受伤动物的血管生成。然而，外周活动对脑缺血后中枢血管生成的治疗作用尚未得到研究。在本项关于小鼠模型中触须-桶状皮层缺血的研究中，我们检验了这样一个假设，即增强触须活动以及对缺血桶状皮层的感觉输入可能会促进缺血后脑血管生成。成年小鼠局灶性缺血三天后，通过两种方法刺激与缺血桶状皮层相对应的触须：（1）修剪小鼠面部右侧的触须，使动物过度使用左侧触须；（2）手动刺激左侧触须以增强对缺血桶状皮层的输入信号。蛋白质免疫印迹分析表明，触须刺激增加了血管生成因子血管内皮生长因子、碱性成纤维细胞生长因子、Tie-1、血管生成素-2（Ang-2）以及可能还有Ang-1的表达。用增殖标志物（5-溴-2'-脱氧尿苷（BrdU））和血管内皮细胞标志物（葡萄糖转运蛋白-1/CD-31）进行共免疫染色，确定了半暗带区域的血管增殖。触须刺激使缺血后7天和14天该区域的BrdU阳性内皮细胞和血管增加。触须刺激还减轻了内皮细胞死亡并增加了局部脑血流量。我们的数据表明，适当增强对缺血皮层的外周活动和传入信号可以促进缺血后血管生成，这可能意味着特定物理治疗对缺血性中风长期恢复具有有益作用。
