Up-regulation of VEGF by retinoic acid during hyperoxia prevents retinal neovascularization and retinopathy.
Up-regulation of VEGF by retinoic acid during hyperoxia prevents retinal neovascularization and retinopathy.
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DOI：
10.1167/iovs.14-14170
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发表时间：
2014-05
影响因子：
4.4
通讯作者：
Liya Wang;Pingling Shi;Zhong-zhong Xu;Jing Li;Yanting Xie;K. Mitton;K. Drenser;Q. Yan
中科院分区：
文献类型：
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作者：
Liya Wang;Pingling Shi;Zhong-zhong Xu;Jing Li;Yanting Xie;K. Mitton;K. Drenser;Q. Yan
早产儿视网膜病变（ROP）与早产儿视网膜血管内皮生长因子（VEGF）表达异常直接相关。本研究旨在探讨全身给予维甲酸（RA）是否能调节视网膜VEGF的表达，并预防氧诱导的视网膜病变（OIR）小鼠模型中视网膜新生血管和视网膜病变。方法C57 BL/6小鼠出生后7 ~ 12日龄暴露于75%氧环境中，观察OIR对小鼠的影响。从P6至P9每天腹腔注射RA。采用全视网膜染色、图像分析、免疫组化、Western blotting、定量RT-PCR、TUNEL法和视网膜电图等方法，观察RA对VEGF表达、视网膜新生血管形成和视网膜神经元功能的影响。结果全身给予维甲酸可促进OIR小鼠视网膜I期VEGF mRNA和蛋白表达，I期VEGF水平稳定，可支持OIR小鼠视网膜血管发育，对抗血管闭塞。随后，II期VEGF的过度生成减弱，视网膜血管渗漏和凋亡细胞明显改善。因此，RA显着防止OIR小鼠缺氧诱导的视网膜新生血管和视网膜病变的发展，并改善光感受器细胞下游的视网膜神经元的功能恢复，如通过局灶视网膜电图测量。结论：全身给予维甲酸可调节OIR小鼠视网膜VEGF的表达，促进视网膜血管的发育。我们建议，在氧疗期间对极低出生体重早产儿全身给予RA可能是预防ROP的有效治疗方法。
PURPOSE Retinopathy of prematurity (ROP) is directly associated with abnormal expression of retinal vascular endothelial growth factor (VEGF) in premature neonates. This study was to investigate whether the systemic administration of retinoic acid (RA) regulates retinal VEGF expression and prevents retinal neovascularization and retinopathy in the oxygen-induced retinopathy (OIR) mouse model. METHODS C57BL/6 mice were subjected to OIR by exposure to 75% oxygen from postnatal day (P) 7 to 12 of age. RA was intraperitoneally injected daily to pups from P6 to P9. Retinal whole mount staining and image analysis, immunostaining, Western blotting, quantitative RT-PCR, TUNEL assay, and electroretinography were performed to evaluate the effects of RA on VEGF expression, retinal neovascularization, and retinal neuron functions. RESULTS Systemic administration of RA in OIR mice promoted retinal VEGF mRNA and protein expression in phase I; the stabilized level of VEGF in phase I supported retinal vascular development and counteracted vaso-obliteration in OIR mice. Subsequently, the excessive generation of VEGF in phase II was attenuated; the retinal vascular leakage and apoptotic cells were significantly ameliorated. As a result, RA significantly prevented the development of hypoxia-induced retinal neovascularization and retinopathy in OIR mice and improved the functional recovery of retinal neurons downstream of photoreceptor cells as measured by focal electroretinography. CONCLUSIONS Systemic administration of RA regulates retinal VEGF expression and supports retinal vascular development in OIR mouse model. We propose that systemic administration of RA to extremely low birth weight, preterm infants during oxygen therapy could potentially be an effective therapeutic approach for the prevention of ROP.