Zhu Tong, Zhu Jie, Bu Xin, Zhao Hu, Zhang Shuya, Chang Yuan, Li Rong, Yao Libo, Wang Yusheng, Su Jin
Department of Ophthalmology, Xijing Hospital, The Fourth Military Medical University, 169 Changle Western Road, Xi'an, 710032, China.
J Mol Med (Berl). 2015 Feb;93(2):187-98. doi: 10.1007/s00109-014-1213-7. Epub 2014 Oct 30.
Choroidal neovascularization (CNV), an aberrant growth of blood vessels in the choroid layer of the eye, is a major cause of vision loss. In view of our recent finding that discoidin domain receptor 2 (DDR2), a collagen-binding receptor tyrosine kinase, is involved in control of vascular endothelial activity and tumor angiogenesis, the present study aims to investigate whether and how DDR2 affects the pathogenesis of CNV. We initially found that a spontaneous DDR2 mutant mouse colony (slie) exhibited enhanced amplitude of laser-induced CNV. The inhibitory role of DDR2 in CNV development was further confirmed by experiments through intravitreous injection of DDR2 small interference RNA (siRNA) or DDR2-expressing adenovirus. Quantitative real-time polymerase chain reaction (qPCR) and immunoblot analysis showed that DDR2 regulates the expression of several major pro-angiogenic factors in the laser-injured choroid as well as in retinal pigment epithelium (RPE) cells. In addition, it was demonstrated that the CNV-induced increases in the phosphorylation levels of Akt and mTOR were affected by the upregulation or downregulation of DDR2. Thus, the data from this study for the first time revealed that DDR2 negatively regulates the development of experimental CNV in vivo, which may provide a novel target for preventing human pathological ocular neovascularization. Key messages: DDR2 does not affect retinal development. DDR2 inhibits laser-induced CNV. DDR2 regulates angiogenic factor expression in CNV lesion as well as in RPE cells. DDR2 is involved in modulation of CNV-induced activation of PI3K pathway.
脉络膜新生血管（CNV）是眼部脉络膜层血管的异常生长，是视力丧失的主要原因。鉴于我们最近发现盘状结构域受体2（DDR2），一种胶原结合受体酪氨酸激酶，参与控制血管内皮活性和肿瘤血管生成，本研究旨在探讨DDR2是否以及如何影响CNV的发病机制。我们最初发现一个自发的DDR2突变小鼠群体（slie）表现出激光诱导的CNV幅度增强。通过玻璃体内注射DDR2小干扰RNA（siRNA）或表达DDR2的腺病毒进行实验，进一步证实了DDR2在CNV发展中的抑制作用。定量实时聚合酶链反应（qPCR）和免疫印迹分析表明，DDR2调节激光损伤脉络膜以及视网膜色素上皮（RPE）细胞中几种主要促血管生成因子的表达。此外，还证明了CNV诱导的Akt和mTOR磷酸化水平的增加受DDR2上调或下调的影响。因此，本研究的数据首次揭示DDR2在体内对实验性CNV的发展具有负调控作用，这可能为预防人类病理性眼部新生血管形成提供一个新靶点。关键信息：DDR2不影响视网膜发育。DDR2抑制激光诱导的CNV。DDR2调节CNV病变以及RPE细胞中血管生成因子的表达。DDR2参与调节CNV诱导的PI3K途径激活。
