Netrin-4 enhances angiogenesis and neurologic outcome after cerebral ischemia
Netrin-4 enhances angiogenesis and neurologic outcome after cerebral ischemia
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DOI：
10.1038/jcbfm.2008.128
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发表时间：
2009-02-01
影响因子：
6.3
通讯作者：
Steinberg, Gary K.
中科院分区：
文献类型：
--
作者：
Hoang, Stanley;Liauw, Jason;Steinberg, Gary K.
脑缺血后的功能恢复是由血管网络的再生和突触结构的恢复介导的。网络蛋白与神经元寻径和血管生成有关。在本研究中，我们研究了小鼠大脑中远端动脉闭塞后，在结直肠癌（DCC）中缺失的Netrin-4及其可能的受体、Unc5A和Unc5B的表达。脑室内注射Netrin-4蛋白，观察其对血管生成和行为恢复的影响。Netrin-4蛋白在脑缺血后第1天在缺血核心高度上调，1周后下调。其表达仅限于血脑屏障损伤区域，在血管和星形细胞足突上均可见。尽管推测的Netrin-4受体Unc5A和Unc5B没有明显上调，但在梗死周围皮层的神经元过程中，DCC受体的表达显著增加。脑室内给药Netrin-4可增加缺血性脑的血管密度、内皮细胞增殖，并在脑卒中后1周改善行为恢复，但对血脑屏障通透性或梗死面积没有影响。这些发现表明Netrin-4可能通过促进血管增殖来改善脑卒中后功能恢复。
Functional recovery after cerebral ischemia is mediated by the regeneration of vascular networks and the restoration of synaptic architecture. Netrins have been implicated in neuronal pathfinding and angiogenesis. In this study, we investigated the expression of Netrin-4 and its putative receptors, deleted in colorectal cancer (DCC), Unc5A, and Unc5B after distal middle cerebral artery occlusion in mice. Netrin-4 protein was also administered intracerebroventricularly to examine its effect on angiogenesis and behavioral recovery. Netrin-4 protein was highly upregulated in the ischemic core as soon as 1 day after cerebral ischemia, with subsequent downregulation after 1 week. Its expression was limited to the area of blood-brain barrier damage and was seen on both blood vessels and astrocytic foot processes. Although there was not a significant upregulation of the putative Netrin-4 receptor Unc5A and Unc5B, there was a significant increase in expression of the DCC receptor on neuronal processes in the peri-infarct cortex. Intracerebroventricular administration of Netrin-4 into the ischemic brain increased blood vessel density, endothelial proliferation, and improved behavioral recovery at 1 week after stroke, but did not have an effect on blood-brain barrier permeability or infarct size. These findings suggest that Netrin-4 may improve poststroke functional recovery by enhancing blood vessel proliferation.