NADPH oxidase 4-derived H2O2 promotes aberrant retinal neovascularization via activation of VEGF receptor 2 pathway in oxygen-induced retinopathy.
NADPH oxidase 4-derived H2O2 promotes aberrant retinal neovascularization via activation of VEGF receptor 2 pathway in oxygen-induced retinopathy.
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DOI：
10.1155/2015/963289
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发表时间：
2015
影响因子：
4.3
通讯作者：
Zhang SX
中科院分区：
文献类型：
--
作者：
Li J;Wang JJ;Zhang SX
NADPH氧化酶4（Nox 4）是视网膜内皮细胞中NADPH氧化酶的主要亚型。我们以前的研究表明，视网膜内皮细胞中Nox 4的上调有助于糖尿病视网膜血管渗漏。在目前的研究中，我们研究了Nox 4在视网膜新生血管（NV），增殖性糖尿病视网膜病变（PDR）的标志，使用氧诱导的视网膜病变（OIR）的小鼠模型的调节的作用和机制。我们的结果证实，Nox 4主要表达在小鼠视网膜的视网膜血管。OIR时视网膜Nox 4的表达显著增加，与ERK磷酸化水平的增强平行。在人视网膜微血管内皮细胞（HREC）中，腺病毒过表达Nox 4显著增加细胞外H2 O2的产生，导致VEGF 2活化增强，并加剧VEGF刺激后的血管生成。与此相反，沉默Nox 4的表达或清除过氧化氢的聚乙二醇（PEG-）结合的过氧化氢酶抑制内皮细胞迁移，管的形成，和VEGF诱导的激活VEGFR 2信号。更重要的是，通过腺病毒介导的siRNA敲低视网膜Nox 4可显著降低ERK的激活，并减弱OIR中视网膜NV的形成。减少视网膜Nox 4表达可能代表了一种有前途的治疗方法，用于新生血管性视网膜疾病，如PDR。
NADPH oxidase 4 (Nox4) is a major isoform of NADPH oxidase in retinal endothelial cells. Our previous study suggests that upregulation of Nox4 in retinal endothelial cells contributes to retinal vascular leakage in diabetes. In the current study, we investigated the role and mechanism of Nox4 in regulation of retinal neovascularization (NV), a hallmark of proliferative diabetic retinopathy (PDR), using a mouse model of oxygen-induced retinopathy (OIR). Our results confirmed that Nox4 was expressed predominantly in retinal vasculature of mouse retina. Retinal expression of Nox4 was markedly increased in OIR, in parallel with enhanced phosphorylation of ERK. In human retinal microvascular endothelial cells (HRECs), overexpression of Nox4 by adenovirus significantly increased extracellular H2O2 generation, resulting in intensified VEGFR2 activation and exacerbated angiogenesis upon VEGF stimulation. In contrast, silencing Nox4 expression or scavenging H2O2 by polyethylene glycol- (PEG-) conjugated catalase inhibited endothelial migration, tube formation, and VEGF-induced activation of VEGFR2 signaling. Importantly, knockdown of retinal Nox4 by adenovirus-delivered siRNA significantly reduced ERK activation and attenuated retinal NV formation in OIR. Taken together, our data indicate that Nox4 promotes retinal NV formation through H2O2/VEGFR2/ERK signaling pathway. Reducing retinal Nox4 expression may represent a promising therapeutic approach for neovascular retinal diseases such as PDR.
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