AAV-mediated netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke.
AAV-mediated netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke.
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DOI：
10.1016/j.nbd.2011.06.006
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发表时间：
2011-10
影响因子：
6.1
通讯作者：
Liu, Jialing
中科院分区：
文献类型：
--
作者：
Sun, Hui;Le, Thang;Chang, Tiffany T. J.;Habib, Aisha;Wu, Steven;Shen, Fanxia;Young, William L.;Su, Hua;Liu, Jialing
除了其在轴突导向中的作用之外，netrin-1还已知是促血管生成的。本研究的目的是确定腺相关病毒（AAV）介导的netrin-1过表达是否改善卒中后神经血管结构和功能恢复。采用大脑中动脉远端闭塞（MCAO）方法，在缺血再灌注后1小时，将1×1010拷贝的AAV-Netrin-1或AAV-LacZ分别注射到缺血损伤的内侧和后侧。定量RT-PCR显示netrin-1转基因的表达最早开始于1天，并在载体注射后约3周显著增加。Western blot分析和共聚焦显微镜显示，内源性和转导的netrin-1在MCAO后梗死周围皮层的神经元中表达。AAV介导的netrin-1过表达显著增加了梗死周围皮质的血管密度，并促进未成熟神经元迁移到梗死周围白色物质中，但它并没有显著减少梗死面积。Netrin-1过表达还增强了中风后的运动活动，改善了探索行为，并减少了缺血诱导的前肢运动不对称。但对脑卒中后空间学习记忆的影响不大。我们的研究结果表明，AAV介导的netrin-1过表达改善梗死周围血管密度和中风后运动功能。
Apart from its role in axon guidance, netrin-1 is also known to be pro-angiogenic. The aim of this study is to determine whether adeno-associated viral (AAV) mediated overexpression of netrin-1 improves post-stroke neurovascular structure and recovery of function. AAV-Netrin-1 or AAV-LacZ of 1×1010 genome copies each was injected medial and posterior to ischemic lesion at one hour following reperfusion using the distal middle cerebral artery occlusion (MCAO) method. Quantitative RT-PCR revealed that the expression of netrin-1 transgene began as early as one day and increased dramatically about 3 weeks following vector injection. Western blot analysis and confocal microscopy suggested that both the endogenous and transduced netrin-1 were expressed in the neurons of the peri-infarct cortex after MCAO. AAV-mediated netrin-1 overexpression significantly increased vascular density in the peri-infarct cortex and promoted the migration of immature neurons into the peri-infarct white matter, but it did not significantly reduce infarct size. Netrin-1 overexpression also enhanced post-stroke locomotor activity, improved exploratory behavior, and reduced ischemia-induced motor asymmetry in forelimb usage. However, it had little effect on post-stroke spatial learning and memory. Our results suggest that AAV mediated netrin-1 overexpression improves peri-infarct vascular density and post stroke motor function.
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