眼内注射贝伐单抗抑制氧诱导视网膜病变模型新生血管形成和血管内皮生长因子异构体的促/抗血管生成表达转换。

Inhibition of neovascularization and expression shift of pro-/anti-angiogenic vascular endothelial growth factor isoforms after intravitreal bevacizumab injection in oxygen-induced-retinopathy mouse model.

机构信息

Department of Ophthalmology, Ministry of Education, Beijing 100044, China.

出版信息

Chin Med J (Engl). 2013 Jan;126(2):345-52.

Abstract

BACKGROUND

Retinopathy of prematurity (ROP) has become one of the leading causes of visual loss in children. Vascular endothelial growth factor A (VEGF-A) is the principal stimulator of angiogenesis. VEGF was differentially spliced from exon 8 to exons 8a and 8b to form two families: the pro-angiogenic VEGFxxx family and the anti-angiogenic VEGFxxxb family. Previous research has shown variable effeteness of bevacizumab in inhibiting retinal neovascularization in ROP. This study aimed to investigate whether the effectiveness of this inhibition depends on the relative ratio of the two VEGF isoforms.

METHODS

Intravitreal bevacizumab injection (IVB) was performed in the oxygen-induced-retinopathy (OIR) mice on postnatal day 12 (P12) (intravitreal phosphate buffered saline (PBS) injection as control). The Evans blue perfused retina were used to test the retinal neovascularization-leakage (NVL) area and non-perfusion (NP) area.

RESULTS

The retinal NVL and NP area in the IVB group were significantly smaller than the intravitreal PBS injection group (IVP group). On P17, the protein level of total VEGF isoforms was significantly inhibited compared to IVP group (P < 0.05) while VEGF(165)b isoform was slight reduced (P > 0.05). The switch from pro-angiogenic isoforms to anti-angiogenic isoforms after IVB could be found. The relative protein expression of VEGF(165)b isoform was significantly higher in IVB group than in IVP group (P < 0.05) on P17 which was correlated with the reduced ischemia-induced angiogenesis in OIR mice after IVB.

CONCLUSIONS

The anti-angiogenic effectiveness might depend on the relative high expression of VEGF(165)b after intravitreal bevacizumab injection. Anti-angiogenic therapy is a more effective therapy for ROP.

摘要

背景

早产儿视网膜病变（ROP）已成为儿童视力丧失的主要原因之一。血管内皮生长因子 A（VEGF-A）是血管生成的主要刺激物。VEGF 通过从外显子 8 到外显子 8a 和 8b 的差异剪接形成两个家族：促血管生成的 VEGFxxx 家族和抗血管生成的 VEGFxxxb 家族。先前的研究表明贝伐单抗抑制 ROP 视网膜新生血管化的效果不同。本研究旨在探讨这种抑制作用的效果是否取决于两种 VEGF 同工型的相对比例。

方法

在出生后第 12 天（P12）对氧诱导视网膜病变（OIR）小鼠进行玻璃体内贝伐单抗注射（IVB）（玻璃体内磷酸盐缓冲盐水（PBS）注射作为对照）。用 Evans 蓝灌注视网膜检测视网膜新生血管渗漏（NVL）区和无灌注（NP）区。

结果

IVB 组的视网膜 NVL 和 NP 区明显小于玻璃体内 PBS 注射组（IVP 组）。在 P17 时，与 IVP 组相比，总 VEGF 同工型的蛋白水平显著降低（P < 0.05），而 VEGF（165）b 同工型略有降低（P > 0.05）。在 IVB 后可以发现从促血管生成同工型向抗血管生成同工型的转换。在 P17 时，IVB 组的 VEGF（165）b 同工型的相对蛋白表达明显高于 IVP 组（P < 0.05），这与 IVB 后 OIR 小鼠缺血诱导的血管生成减少有关。