ISCHEMIC TOLERANCE IS ASSOCIATED WITH VEGF-C AND VEGFR-3 SIGNALING IN THE MOUSE HIPPOCAMPUS
ISCHEMIC TOLERANCE IS ASSOCIATED WITH VEGF-C AND VEGFR-3 SIGNALING IN THE MOUSE HIPPOCAMPUS
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DOI：
10.1016/j.neuroscience.2015.01.025
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发表时间：
2015-04-02
期刊：
影响因子：
3.3
通讯作者：
Kim, S. Y.
中科院分区：
文献类型：
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作者：
Bhuiyan, M. I. H.;Kim, J. -C.;Kim, S. Y.
血管内皮生长因子C（VEGF-C）和VEGF受体3（VEGFR-3）在神经系统中的功能尚不清楚。在这项研究中，我们研究了VEGF-C和VEGFR-3在缺血预处理（IPC）诱导的小鼠海马耐受中的作用。成年雄性C57 BL/6小鼠经受通过双侧颈总动脉闭塞（BCCAO）40分钟伴或不伴IPC（5分钟BCCAO）或仅IPC诱导的严重缺血（SI）。在缺血期间使用激光多普勒血流仪测量脑血流量。神经元损伤进行了组织学评估，VEGF-C和VEGFR-3的表达水平进行了评估，通过免疫染色。Fluoro-Jade B-标记的细胞在SI后7天在没有IPC的情况下（sham + SI组）在CA 1区中丰富，而在经受IPC然后SI的小鼠中（IPC + SI组）细胞很少被标记。同样，假手术+ SI组中CA 1区神经元核（NeuN）阳性细胞的数量显著低于IPC + SI组。有趣的是，我们发现亚致死IPC治疗诱导CA 1锥体神经元中显著的VEGF-C表达和放射层和腔隙分子层中的VEGFR-3表达，再灌注3天后持续7天。此外，VEGF-C免疫反应性也显着增加，而VEGFR-3的表达持续在耐受性获得的CA 1神经元后SI。应用VEGFR-3抑制剂SAR 131675以剂量依赖性方式消除小鼠海马中IPC诱导的神经保护作用。这些结果表明，VEGF-C/VEGFR 3信号与IPC诱导的海马耐受致死性缺血。(C)2015年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The functions of vascular endothelial growth factor C (VEGF-C) and the VEGF receptor 3 (VEGFR-3) in the nervous system are not well known. In this study, we examined the role of VEGF-C and VEGFR-3 in ischemic preconditioning (IPC)-induced tolerance in the mouse hippocampus. Adult male C57BL/6 mice were subjected to either severe ischemia (SI) induced by 40 min of bilateral common carotid artery occlusion (BCCAO) with or without IPC (5-min BCCAO) or IPC only. Cerebral blood flow was measured during ischemic periods using laser Doppler flowmetry. Neuronal damage was assessed histologically, and VEGF-C and VEGFR-3 expression levels were assessed through immunostaining. Fluoro-Jade B-labeled cells were abundant in the CA1 area 7 days after SI without IPC (sham + SI group), whereas cells were rarely labeled in mice subjected to IPC followed by SI (IPC + SI group). Similarly, the number of neuronal nuclei (NeuN)-positive cells in the CA1 area was significantly lower in the sham + SI group than in the IPC + SI group. Interestingly, we found that sublethal IPC treatment induced prominent VEGF-C expression in the CA1 pyramidal neurons and VEGFR-3 expression in the stratum radiatum and stratum lacunosum moleculare after 3 days of reperfusion that were sustained for 7 days. Moreover, VEGF-C immunoreactivity was also markedly increased, whereas VEGFR-3 expression was sustained in tolerance-acquired CA1 neurons after SI. Application of a VEGFR-3 inhibitor, SAR131675, abolished the IPC-induced neuroprotection in a dose-dependent manner in the mouse hippocampus. These results suggest that VEGF-C/VEGFR3 signaling is associated with IPC-induced hippocampal tolerance to lethal ischemia. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.