Bidirectional communication between neurons and vascular cells is important to the maintenance of the central nervous system (CNS) milieu. Vascular endothelial growth factor (VEGF), through its ability to affect both vascular and neuronal cells, is likely a key protein in this process. Despite considerable literature documenting a neuroprotective function for VEGF, overexpression of this protein has also been shown in a wide variety of CNS diseases, including Alzheimer's disease (AD). Increased oxidative stress and elevated thrombin levels have also been documented in AD, specifically in the microvasculature. The aim of the current study is to examine endothelial cells and neurons in vitro to determine the effects of oxidative stress and thrombin on VEGF release as well as the effects of low and high dose VEGF on neuronal viability. The data show that microvessels isolated from AD patients secrete significantly higher levels of VEGF compared to control-derived vessels. Exposure of brain endothelial cells to oxidative stress (sodium nitroprusside, menadione, or hydrogen peroxide) or thrombin significantly increases VEGF expression. Exposure of cultured neurons to oxidative stress increases expression of thrombin. Treating rat cortical neurons with high dose VEGF (≥500 ng/ml) decreases neuronal survival and expression of the anti-apoptotic protein Bcl-2 while increasing proapoptic proteins caspase 3 and phosphorylated p38 MAPK. High dose VEGF also negates the decrease in amyloid-β evoked by low dose VEGF. These results suggest that despite literature supporting neuroprotective effects of this protein, caution is warranted prior to implementation of VEGF as a therapeutic in the brain.

译文

神经元和血管细胞之间的双向通信对于维持中枢神经系统 (CNS) 环境很重要。血管内皮生长因子 (VEGF) 通过其同时影响血管和神经元细胞的能力,可能是此过程中的关键蛋白。尽管有大量文献记录了VEGF的神经保护功能,但该蛋白的过表达也已在包括阿尔茨海默氏病 (AD) 在内的多种中枢神经系统疾病中显示。在AD中,特别是在微血管系统中,也记录了氧化应激增加和凝血酶水平升高。当前研究的目的是在体外检查内皮细胞和神经元,以确定氧化应激和凝血酶对VEGF释放的影响以及低剂量和高剂量VEGF对神经元活力的影响。数据显示,与对照来源的血管相比,从AD患者中分离出的微血管分泌的VEGF水平明显更高。脑内皮细胞暴露于氧化应激 (硝普钠,甲萘醌或过氧化氢) 或凝血酶会显着增加VEGF的表达。培养的神经元暴露于氧化应激会增加凝血酶的表达。用高剂量VEGF (≥ 500 ng/ml) 处理大鼠皮质神经元会降低神经元存活和抗凋亡蛋白Bcl-2的表达,同时增加促凋亡蛋白caspase 3和磷酸化p38mapk。高剂量VEGF也抵消了低剂量VEGF引起的淀粉样蛋白 β 的减少。这些结果表明,尽管有文献支持该蛋白的神经保护作用,但在将VEGF用作大脑治疗药物之前还是要谨慎。

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