The effect of recombinant human erythropoietin on neurovasculature repair after focal ischemic stroke in neonatal rats
The effect of recombinant human erythropoietin on neurovasculature repair after focal ischemic stroke in neonatal rats
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DOI：
10.1124/jpet.107.121392
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Wei, Ling
中科院分区：
文献类型：
--
作者：
Keogh, Christine L.;Yu, Shan Ping;Wei, Ling
脑缺血会破坏神经血管单位，导致核心区和半影区的神经元、神经胶质细胞和内皮细胞 (EC) 死亡。尽管重组人促红细胞生成素 (rhEPO) 的神经保护作用已被广泛研究，但其对 EC 的影响仍然难以捉摸。我们现在报告rhEPO治疗对出生后第7天新生大鼠局灶性缺血性中风后EC死亡和神经血管修复的影响。缺血后 60 分钟和接下来的 3 天给予 rhEPO（5000 U/kg i.p.）。蛋白质印迹分析显示，在rhEPO处理的幼犬中，神经血管重塑蛋白的表达增加，包括Tie-1、血管生成素-2和碱性成纤维细胞生长因子。通过末端脱氧核苷酸转移酶 dUTP 缺口末端标记和 EC 标记葡萄糖转运蛋白 1 (GLUT-1) 的免疫染色检查，缺血后 12 至 72 小时，rhEPO 治疗显着减少了缺血半暗带区域的 EC 死亡。中风后 7 至 21 天，5-溴-2'-脱氧尿苷与 GLUT-1 或神经元标记蛋白 (NeuN) 共染色显示，rhEPO 治疗可增加 EC 和神经元细胞的增殖。具体来说，rhEPO 增加了靠近增殖微血管的 NeuN 阳性细胞的数量。这些结果首次表明，除了对神经细胞的保护之外，EPO还可以保护EC并促进神经血管单元修复，这可能有助于其在新生儿缺血性中风后的治疗效果。
Cerebral ischemia disrupts the neurovascular unit, involving death of neuronal, glial, and endothelial cells (ECs) in the core and penumbra regions. Whereas the neuroprotective effect of recombinant human erythropoietin (rhEPO) has been widely investigated, its effects on ECs remain elusive. We now report the effects of rhEPO treatment on EC death and neurovasculature repair following a focal ischemic stroke in postnatal day 7 neonatal rats. rhEPO (5000 U/kg i.p.) was administered 60 min after ischemia and for the next 3 days. Western blot analysis revealed increased expression of neurovascular remodeling proteins, including Tie-1, angiopoietin-2, and basic fibroblast growth factor in rhEPO-treated pups. rhEPO treatment significantly reduced EC death in the ischemic penumbra region 12 to 72 h after ischemia examined by immunostaining of terminal deoxynucleotidyl transferase dUTP nick-end labeling and EC marker glucose transporter-1 (GLUT-1). Treatment with rhEPO increased proliferation of ECs and neuronal cells, revealed by costaining of 5-bromo-2'-deoxyuridine with GLUT-1 or with the neuronal marker protein (NeuN) 7 to 21 days after stroke. Specifically, rhEPO increased number of NeuN-positive cells in close proximity to proliferating microvessels. These results suggest for the first time that, in addition to its protection on neural cells, EPO protects ECs and promotes the neurovascular unit repair, which may contribute to its therapeutic benefits after neonatal ischemic stroke.