Wang Yaoming, Jin Kunlin, Mao Xiao Ou, Xie Lin, Banwait Surita, Marti Hugo H, Greenberg David A
Buck Institute for Age Research, Novato, California 94945, USA.
J Neurosci Res. 2007 Mar;85(4):740-7. doi: 10.1002/jnr.21169.
New neurons are generated continuously in the subventricular zone and dentate gyrus of the adult brain. Neuropathologic processes, including cerebral ischemia, can enhance neurogenesis, as can growth factors and other physiologic stimuli. Vascular endothelial growth factor (VEGF) is an angiogenic and neuroprotective growth factor that can promote neurogenesis, but it is unknown whether VEGF can enhance migration of newborn neurons toward sites of ischemic injury, where they might be able to replace neurons that undergo ischemic death. In the present study we produced permanent focal cerebral ischemia in transgenic (Tg) mice that overexpress VEGF. Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (Brdu) labeling and immunostaining for cell type-specific markers. In VEGF-Tg mice, brains examined 7-28 days after cerebral ischemia showed markedly increased subventricular zone (SVZ) neurogenesis, chains of neuroblasts extending from the SVZ to the peri-infarct cortex, and an increase in the number of newly generated cortical neurons at 14-28 days after ischemia. In concert with these effects, VEGF overexpression reduced infarct volume and improved postischemic motor function. These findings provide evidence that VEGF increases SVZ neurogenesis and neuromigration, consistent with a possible role in repair. Our data suggest that in addition to its neuroprotective effects, which are associated with improved outcome in the acute phase after cerebral ischemia, VEGF enhances postischemic neurogenesis, which could provide a therapeutic target for more chronic brain repair.
成人大脑的脑室下区和齿状回中持续生成新的神经元。包括脑缺血在内的神经病理过程可增强神经发生，生长因子和其他生理刺激也能如此。血管内皮生长因子（VEGF）是一种具有血管生成和神经保护作用的生长因子，可促进神经发生，但VEGF是否能增强新生神经元向缺血损伤部位的迁移尚不清楚，而在这些部位新生神经元或许能够替代因缺血而死亡的神经元。在本研究中，我们在过度表达VEGF的转基因（Tg）小鼠中制造了永久性局灶性脑缺血。通过溴脱氧尿苷（Brdu）标记和针对细胞类型特异性标志物的免疫染色来评估细胞增殖和神经发生。在VEGF-Tg小鼠中，脑缺血后7 - 28天检查的大脑显示脑室下区（SVZ）神经发生显著增加，神经母细胞链从SVZ延伸至梗死灶周围皮质，且缺血后14 - 28天新生成的皮质神经元数量增加。与这些效应一致，VEGF过表达减少了梗死体积并改善了缺血后运动功能。这些发现提供了证据表明VEGF增加了SVZ神经发生和神经迁移，这与它在修复中可能发挥的作用相符。我们的数据表明，除了其神经保护作用（这与脑缺血急性期预后改善相关）外，VEGF还增强了缺血后神经发生，这可能为更慢性的脑修复提供一个治疗靶点。
