Li Weijing, Zhang Weihua, Zhang Cuiying, Zhu Chunfang, Yi Xiangling, Zhou Yan, Lv Yan
Department of Ophthalmology, Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China.
Exp Ther Med. 2019 Jul;18(1):614-620. doi: 10.3892/etm.2019.7608. Epub 2019 May 24.
The aim of the present study was to investigate the potential mechanism of retinopathy of prematurity (ROP) using an oxygen-induced retinopathy (OIR) mouse model. For experiments, mice were divided into either the OIR group or control group. Fluorescein isothiocyanate-dextran cardiac perfusion and stretched retina preparation were performed. The total retina area, area of instillation, density of microvascular network, area of new blood vessels, vein width and the tortuosity of arteries were measured. Next, mice were randomly assigned into the PBS, soluble TEK receptor tyrosine kinase (sTie2)-fusion protein (Fc), angiopoietin 1 (Ang1), ranibizumab, ranibizumab + sTie2-Fc and ranibizumab + Ang1 treatment groups. Following housing for 5 days, the body weight of each mouse was recorded. Mice in the OIR group presented smaller total retina area and larger area of instillation, larger area of new blood vessels, and higher microvascular network density compared with the control PBS group. Obvious retinal vein dilatation and arterial tortuosity were identified in the OIR group. The amount of endotheliocyte nuclei of new vessels beyond the inner limiting membrane was larger in the OIR group compared with the control group. Furthermore in the next set of experiments, a larger area of instillation, smaller area of new blood vessels and decreased amount of endotheliocyte nuclei of new vessels were observed in the sTie2-Fc group, Ang1 group, ranibizumab group, ranibizumab + sTie2-Fc group and ranibizumab + Ang1 group compared with the PBS group. Specifically, the ranibizumab + sTie2-Fc group and ranibizumab + Ang1 group demonstrated markedly reduced retina instillation area and microvascular network density in the instillation area. Total retina area and body weight following 10 days of the experiment for the ranibizumab group were significantly lower compared with other groups. In conclusion, the combined regulation of the Ang/Tie2 and the vascular endothelial growth factor (VEGF)/VEGF receptor pathways markedly increased the efficacy of treatment with retinal neovascularization (RNV). Regulation of these pathways has a potential for treating RNV, in particular ROP.
本研究的目的是利用氧诱导视网膜病变（OIR）小鼠模型探究早产儿视网膜病变（ROP）的潜在机制。实验中，将小鼠分为OIR组或对照组。进行异硫氰酸荧光素-葡聚糖心脏灌注和拉伸视网膜制备。测量视网膜总面积、滴注面积、微血管网络密度、新生血管面积、静脉宽度和动脉迂曲度。接下来，将小鼠随机分为PBS、可溶性TEK受体酪氨酸激酶（sTie2）-融合蛋白（Fc）、血管生成素1（Ang1）、雷珠单抗、雷珠单抗+sTie2-Fc和雷珠单抗+Ang1治疗组。饲养5天后，记录每只小鼠的体重。与对照PBS组相比，OIR组小鼠的视网膜总面积较小，滴注面积较大，新生血管面积较大，微血管网络密度较高。在OIR组中发现明显的视网膜静脉扩张和动脉迂曲。与对照组相比，OIR组中内界膜以外新生血管的内皮细胞核数量更多。此外，在接下来的一组实验中，与PBS组相比，在sTie2-Fc组、Ang1组、雷珠单抗组、雷珠单抗+sTie2-Fc组和雷珠单抗+Ang1组中观察到滴注面积更大、新生血管面积更小以及新生血管内皮细胞核数量减少。具体而言，雷珠单抗+sTie2-Fc组和雷珠单抗+Ang1组在滴注区域的视网膜滴注面积和微血管网络密度明显降低。与其他组相比，雷珠单抗组实验10天后的视网膜总面积和体重显著更低。总之，Ang/Tie2和血管内皮生长因子（VEGF）/VEGF受体途径的联合调节显著提高了视网膜新生血管（RNV）治疗的疗效。调节这些途径具有治疗RNV尤其是ROP的潜力。
