Long-term continuous corticosterone treatment decreases VEGF receptor-2 expression in frontal cortex.
Long-term continuous corticosterone treatment decreases VEGF receptor-2 expression in frontal cortex.
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DOI：
10.1371/journal.pone.0020198
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Pillai A
中科院分区：
文献类型：
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作者：
Howell KR;Kutiyanawalla A;Pillai A
压力和糖皮质激素水平升高与许多神经精神疾病有关，包括精神分裂症和抑郁症。最近，血管内皮因子受体-2 （VEGFR2/Flk1）信号的作用与应激介导的神经可塑性有关。然而，长期持续糖皮质激素暴露对VEGF/Flk1信号的调控机制尚不清楚。我们研究了长期持续的糖皮质激素暴露对体外培养的皮质神经元、小鼠体内额叶皮层以及对照组和精神分裂症受试者死后的人类前额叶皮层中VEGF/Flk1信号传导的可能影响。我们发现，长期持续暴露于皮质酮（CORT，一种天然糖皮质激素）会降低体外和体内Flk1蛋白水平。CORT处理导致Flk1下游信号分子如PTEN、Akt和mTOR的改变。我们证明了cort诱导的Flk1水平的变化是通过糖皮质激素受体（GR）和钙介导的。在CORT暴露后，观察到Flk1-GR相互作用显著减少。有趣的是，在CORT治疗后，皮质中的VEGF水平升高，但血清中的VEGF水平降低。此外，在精神分裂症受试者的死后前额皮质样本中发现Flk1和GR蛋白水平显著降低。长期持续的CORT暴露后VEGF/Flk1信号的改变代表了慢性应激神经生物学效应的分子机制。
Stress and increased glucocorticoid levels are associated with many neuropsychiatric disorders including schizophrenia and depression. Recently, the role of vascular endothelial factor receptor-2 (VEGFR2/Flk1) signaling has been implicated in stress-mediated neuroplasticity. However, the mechanism of regulation of VEGF/Flk1 signaling under long-term continuous glucocorticoid exposure has not been elucidated. We examined the possible effects of long-term continuous glucocorticoid exposure on VEGF/Flk1 signaling in cultured cortical neurons in vitro, mouse frontal cortex in vivo, and in post mortem human prefrontal cortex of both control and schizophrenia subjects. We found that long-term continuous exposure to corticosterone (CORT, a natural glucocorticoid) reduced Flk1 protein levels both in vitro and in vivo. CORT treatment resulted in alterations in signaling molecules downstream to Flk1 such as PTEN, Akt and mTOR. We demonstrated that CORT-induced changes in Flk1 levels are mediated through glucocorticoid receptor (GR) and calcium. A significant reduction in Flk1-GR interaction was observed following CORT exposure. Interestingly, VEGF levels were increased in cortex, but decreased in serum following CORT treatment. Moreover, significant reductions in Flk1 and GR protein levels were found in postmortem prefrontal cortex samples from schizophrenia subjects. The alterations in VEGF/Flk1 signaling following long-term continuous CORT exposure represents a molecular mechanism of the neurobiological effects of chronic stress.
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DOI：
10.1073/pnas.0709102105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Jeanneteau, Freddy;Garabedian, Michael J.;Chao, Moses V.
通讯作者：
Chao, Moses V.
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
7.6
作者：
Leitch, MM;Ingram, CD;Gartside, SE
通讯作者：
Gartside, SE
DOI：
10.1073/pnas.182296499
发表时间：
2002-09-03
影响因子：
11.1
作者：
Jin, KL;Zhu, YH;Greenberg, DA
通讯作者：
Greenberg, DA
DOI：
10.1038/npp.2009.68
发表时间：
2009-10
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
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作者：
通讯作者：
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