Expression and Cellular Distribution of Vascular Endothelial Growth Factor‐C System in Cortical Tubers of the Tuberous Sclerosis Complex
Expression and Cellular Distribution of Vascular Endothelial Growth Factor‐C System in Cortical Tubers of the Tuberous Sclerosis Complex
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DOI：
10.1111/j.1750-3639.2011.00519.x
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发表时间：
2012-03
期刊：
影响因子：
6.4
通讯作者：
Chun-Qing Zhang;H. Shu;Qing Yin;Ning An;Sen-lin Xu;Jin-bo Yin;Yechun Song;Shiyong Liu;Hui Yang
中科院分区：
文献类型：
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作者：
Chun-Qing Zhang;H. Shu;Qing Yin;Ning An;Sen-lin Xu;Jin-bo Yin;Yechun Song;Shiyong Liu;Hui Yang
皮质结节是结节性硬化症（TSC）患者的皮质发育畸形，与小儿难治性癫痫高度相关。最近的证据表明，通过血管内皮生长因子-C（VEGF-C）及其受体VEGFR-2和VEGFR-3介导的信号传导对神经元和神经胶质细胞都有直接影响。为了了解VEGF-C系统在皮质结节发病机制中的潜在作用，我们研究了VEGF-C信号在皮质结节中的表达模式，并与年龄匹配的正常对照皮质（CTX）进行了比较。我们发现，与CTX相比，VEGF-C，VEGFR-2和VEGFR-3在mRNA和蛋白质水平上在块茎中明显上调。原位杂交和免疫组化结果表明，VEGF-C、VEGFR-2和VEGFR-3在块茎内发育不良的神经元（DN）、巨细胞（GC）和反应性星形胶质细胞中高度表达。大多数表达VEGF-C及其受体的DN/GC与神经元标记物而不是星形胶质细胞标记物共标记，表明神经元谱系。此外，Akt-1、p-Bad和ERK 1/2（VEGF-C通路的重要下游因子）的蛋白水平在皮质块茎中显著增加，表明皮质块茎中涉及VEGF-C依赖性促生存信号传导。综上所述，我们的研究结果表明，VEGF-C信号通路在皮质块茎的发病机制中起着假定的作用。
Cortical tubers are malformations of cortical development in patients with tuberous sclerosis complex (TSC), and highly associated with pediatric intractable epilepsy. Recent evidence has shown that signaling mediated through vascular endothelial growth factor‐C (VEGF‐C) and its receptors, VEGFR‐2 and VEGFR‐3, has direct effects on both neurons and glial cells. To understand the potential role of VEGF‐C system in the pathogenesis of cortical tubers, we investigated the expression patterns of VEGF‐C signaling in cortical tubers compared with age‐matched normal control cortex (CTX). We found that VEGF‐C, VEGFR‐2 and VEGFR‐3 were clearly upregulated in tubers at both the mRNA and protein levels, compared with CTX. The in situ hybridization and immunostaining results demonstrated that VEGF‐C, VEGFR‐2 and VEGFR‐3 were highly expressed in dysplastic neurons (DNs), giant cells (GCs) and reactive astrocytes within tubers. Most DNs/GCs expressing VEGF‐C and its receptors co‐labeled with neuronal rather than astrocytic markers, suggesting a neuronal lineage. In addition, protein levels of Akt‐1, p‐Bad and ERK1/2, the important downstream factors of the VEGF‐C pathway, were significantly increased in cortical tubers, indicating involvement of VEGF‐C–dependent prosurvival signaling in cortical tubers. Taken together, our results suggest a putative role for the VEGF‐C signaling pathway in the pathogenesis of cortical tubers.