抗血管内皮生长因子抗体导致早产儿视网膜病变大鼠模型中晚期非典型玻璃体内新生血管形成和血管生成途径的激活。
Anti-VEGF antibody leads to later atypical intravitreous neovascularization and activation of angiogenic pathways in a rat model of retinopathy of prematurity.
机构信息
Department of Ophthalmology, The John Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA.
出版信息
Invest Ophthalmol Vis Sci. 2013 Mar 21;54(3):2020-6. doi: 10.1167/iovs.13-11625.
PURPOSE
Inhibiting VEGF improves adult retino/choroido-vascular diseases, but can lead to recurrent intravitreous neovascularization (IVNV), avascular retina (AVA), and retinal detachment in preterm infants with retinopathy of prematurity (ROP). We sought to understand causes of late-onset IVNV and AVA following anti-VEGF using an ROP model.
METHODS
In the Penn model of ROP, postnatal day (p)12 pups received 1 μL intravitreal VEGFA164 antibody (anti-VEGF; 25-100 ng) or IgG control in each eye. Analyses included lectin-stained percent IVNV and AVA; VEGF protein, erythropoietin, phosphorylated extracellular signal-related kinases and signal transducer and activator of transcription-3 (p-STAT3); and immunohistochemistry of retinal sections for p-VEGFR2. Western blots of human retinal microvascular endothelial cells (hRMVECs) stimulated with VEGF or erythropoietin were analyzed for p-STAT3. Statistical analysis was performed with one-way ANOVA or two-tailed t-tests.
RESULTS
At p18, 50 ng anti-VEGF reduced IVNV, and at p25, caused increased IVNV and AVA compared with controls. VEGF and p-VEGFR2 labeling increased following 100 ng anti-VEGF. Following 50 ng anti-VEGF, reduced p-STAT3 and increased erythropoietin occurred at p18. Erythropoietin or VEGF stimulated hRMVEC proliferation and STAT3 activation. In vivo, anti-VEGF reduced pup growth.
CONCLUSIONS
Increases in erythropoietin and angiogenic signaling following anti-VEGF may account for recurrent IVNV. Anti-VEGF reduced pup growth. Research is needed regarding safety, dose, and type of antiangiogenic treatment for ROP.
目的
抑制 VEGF 可改善成人视网膜/脉络膜血管疾病，但可能导致早产儿视网膜病变（ROP）患者出现反复性玻璃体内新生血管（IVNV）、无血管视网膜（AVA）和视网膜脱离。我们试图通过 ROP 模型了解抗 VEGF 后迟发性 IVNV 和 AVA 的原因。
方法
在 ROP 的 Penn 模型中，新生后第 12 天（p）的幼鼠每只眼接受 1 μL 玻璃体内 VEGFA164 抗体（抗 VEGF；25-100ng）或 IgG 对照。分析包括用凝集素染色的 IVNV 和 AVA 百分比；VEGF 蛋白、促红细胞生成素、磷酸化细胞外信号相关激酶和信号转导和转录激活因子 3（p-STAT3）；以及用视网膜切片进行 p-VEGFR2 的免疫组织化学染色。用 VEGF 或促红细胞生成素刺激的人视网膜微血管内皮细胞（hRMVEC）的 Western blot 分析 p-STAT3。采用单因素方差分析或双尾 t 检验进行统计学分析。
结果
在 p18 时，50ng 抗 VEGF 减少了 IVNV，而在 p25 时与对照组相比，导致 IVNV 和 AVA 增加。用 100ng 抗 VEGF 处理后，VEGF 和 p-VEGFR2 标记增加。用 50ng 抗 VEGF 处理后，在 p18 时观察到 p-STAT3 减少和促红细胞生成素增加。促红细胞生成素或 VEGF 刺激 hRMVEC 增殖和 STAT3 激活。在体内，抗 VEGF 减少了幼鼠的生长。
结论
抗 VEGF 后促红细胞生成素和血管生成信号的增加可能是反复性 IVNV 的原因。抗 VEGF 减少了幼鼠的生长。需要进一步研究 ROP 抗血管生成治疗的安全性、剂量和类型。
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