Astrocyte growth effects of vascular endothelial growth factor (VEGF) application to perinatal neocortical explants: Receptor mediation and signal transduction pathways
Astrocyte growth effects of vascular endothelial growth factor (VEGF) application to perinatal neocortical explants: Receptor mediation and signal transduction pathways
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DOI：
10.1016/j.expneurol.2004.12.022
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发表时间：
2005-04-01
影响因子：
5.3
通讯作者：
Rosenstein, JM
中科院分区：
文献类型：
--
作者：
Mani, N;Khaibullina, A;Rosenstein, JM
在胎儿和出生后的大鼠大脑皮质器官型外植体中，研究了血管内皮生长因子（VEGF）及其受体flt - 1和flk - 1的非血管生成作用以及下游信号通路。在两种模式下应用VEGF均导致星形胶质细胞增殖显著增加，以及胶质纤维酸性蛋白（GFAP）和巢蛋白免疫反应性呈剂量依赖性增加。在大多数（尽管不是全部）星形胶质细胞上观察到VEGF受体flt - 1，而未观察到flk - 1受体的免疫表达。用针对flt - 1的反义寡核苷酸（AS - ODNs）处理导致GFAP和巢蛋白免疫反应性急剧下降，这进一步证实了flt - 1在介导VEGF的促胶质细胞作用中的角色，而针对flk - 1的AS - ODNs没有作用。发现VEGF诱导的促胶质细胞作用是由丝裂原活化蛋白激酶/细胞外调节蛋白激酶（MAPK/ERK）和磷脂酰肌醇 - 3激酶（PI - 3激酶）信号通路介导的，因为MEK1抑制剂PD98059和PI - 3激酶抑制剂渥曼青霉素都消除了VEGF诱导的星形胶质细胞GFAP（+）表达。尽管高剂量VEGF的应用导致星形胶质细胞中GFAP和巢蛋白免疫反应性都强烈上调，但并非在所有细胞中都观察到这两种蛋白的重叠，这表明一些巢蛋白（+）细胞可能是神经祖细胞。暴露于VEGF导致在1天时间点VEGF和碱性成纤维细胞生长因子（bFGF）mRNA上调，并且在3天时bFGF蛋白上调；被VEGF激活的星形胶质细胞比未处理的外植体中的星形胶质细胞表达bFGF的程度高得多。VEGF诱导的bFGF表达增加可能有助于多能神经干/祖细胞在体外的增殖。VEGF作为一种已确定的血管生成因子，似乎在中枢神经系统中星形胶质细胞的生长和分化中起重要作用。（c）2004爱思唯尔公司。保留所有权利。
The non-angiogenic role of vascular endothelial growth factor (VEGF), and its receptors,flt-1 and flk-1, together with downstream signaling pathways were examined in fetal and postnatal rat cerebral cortical organotypic explants. VEGF application in both paradigms caused a significant increase in astroglial proliferation and a dose-dependent increase in GFAP and nestin immunoreactivity. The VEGF receptor flt-1 was observed on most, though not all astrocytes, while flk-1 receptor immunoexpression was absent. Treatment with antisense oligonucleotides (AS-ODNs) to,flt-1 resulted in a dramatic decrease in GFAP and nestin immunoreactivity, which further confirmed the role of flt-1 in mediating VEGF's gliotrophic effects, while AS-ODNs to flk-1 had no effect. VEGF-induced gliotrophic effects were found to be mediated by the MAPK/ERK and PI-3 kinase signaling pathways, since the both the MEK1 inhibitor, PD98059 and the PI-3 kinase inhibitor, Wortmannin abolished VEGF-induced astrocytic GFAP(+) expression. Although high dose VEGF application resulted in strong upregulation of both GFAP and nestin immunoreactivity in astrocytes, overlap of the two proteins was not observed in all cells, suggesting that some of the nestin(+) cells might be neural progenitors. Exposure to VEGF resulted in upregulation of both VEGF and bFGF mRNA at the one-day time point, and bFGF protein by 3 days; VEGF activated astrocytes expressed bFGF to a much greater degree than those in untreated explants. The increased expression of bFGF induced by VEGF, may serve in the proliferation of multipotential neural stem/progenitor cells in vitro. VEGF, an established angiogenic factor, appears to play a significant role in the growth and differentiation of astrocytes in the CNS. (c) 2004 Elsevier Inc. All rights reserved.