Progressive vision loss in adults has become increasingly prevalent worldwide due to retinopathies associated with aging, genetics, and epigenetic factors that damage the retinal microvasculature. Insufficient supply of oxygen and/or nutrients upregulates factors such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), which can induce abnormal angiogenesis and damage the structural arrangement of the retinal blood barrier (BRB). Müller glia (MG) regulate the diffusion of essential compounds across the BRB and respond to retinal insults via reactive gliosis, which includes cell hypertrophy, migration, and/or proliferation near areas of elevated VEGF concentration. Increasing concentrations of exogenous VEGF, upregulated by retinal pigmented epithelium cells, and endogenous epidermal growth factor receptor (EGF-R) stimulation in MG, implicated in MG proliferative and migratory behavior, often lead to progressive and permanent vision loss. Our project examined the chemotactic responses of the rMC-1 cell line, a mammalian MG model, toward VEGF and EGF signaling fields in transwell assays, and within respective concentration gradient fields produced in the glia line (gLL) microfluidic system previously described by our group. rMC-1 receptor expression in defined ligand fields was also evaluated using quantitative polymerase chain reaction (qPCR) and immunocytochemical staining. Results illustrate dramatic increases in rMC-1 chemotactic responses towards EGF gradient fields after pre-treatment with VEGF. In addition, qPCR illustrated significant upregulation of EGF-R upon VEGF pre-treatment, which was higher than that induced by its cognate ligand, EGF. These results suggest interplay of molecular pathways between VEGF and EGF-R that have remained understudied in MG but are significant to the development of effective anti-VEGF treatments needed for a variety of retinopathies.

中文翻译：

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VEGF上调EGFR表达，以刺激MüllerGlia rMC-1模型的趋化行为。

由于与衰老，遗传学和损害视网膜微脉管系统的表观遗传因素相关的视网膜病变，成人的渐进性视力丧失在世界范围内变得越来越普遍。氧气和/或营养素的不足供应会上调诸如血管内皮生长因子（VEGF）和表皮生长因子（EGF）的因子，这些因子会诱导异常的血管生成并破坏视网膜血屏障（BRB）的结构。Müller胶质细胞（MG）调节重要化合物在BRB中的扩散，并通过反应性胶质增生对视网膜损伤做出反应，这包括细胞肥大，迁移和/或VEGF浓度升高区域附近的增殖。视网膜色素上皮细胞上调增加外源性VEGF的浓度，MG中的内源性表皮生长因子受体（EGF-R）刺激与MG的增殖和迁移行为有关，通常会导致进行性和永久性视力丧失。我们的项目在transwell分析中以及在我们小组先前描述的神经胶质细胞系（gLL）微流体系统中产生的各自浓度梯度场内，研究了哺乳动物MG模型rMC-1细胞系对VEGF和EGF信号场的趋化反应。还使用定量聚合酶链反应（qPCR）和免疫细胞化学染色评估了rMC-1受体在定义的配体区域的表达。结果表明，用VEGF预处理后，rMC-1对EGF梯度场的趋化反应显着增加。此外，qPCR显示VEGF预处理后EGF-R明显上调，高于其同源配体EGF诱导的水平。这些结果表明，MG和EGF-R之间的分子途径之间的相互作用在MG中仍未得到充分研究，但对于开发各种视网膜病所需的有效抗VEGF治疗具有重要意义。