Abstract
Retinopathy of prematurity, formerly known as a retrolental fibroplasia, is a leading cause of infantile blindness worldwide. Retinopathy of prematurity is caused by the failure of central retinal vessels to reach the retinal periphery, creating a nonperfused peripheral retina, resulting in retinal hypoxia, neovascularization, vitreous hemorrhage, vitreoretinal fibrosis, and loss of vision. We established a potential retinopathy of prematurity model by using a green fluorescent vascular endothelium zebrafish transgenic line treated with cobalt chloride (a hypoxia-inducing agent), followed by GS4012 (a vascular endothelial growth factor inducer) at 24 hours postfertilization, and observed that the number of vascular branches and sprouts significantly increased in the central retinal vascular trunks 2–4 days after treatment. We created an angiography method by using tetramethylrhodamine dextran, which exhibited severe vascular leakage through the vessel wall into the surrounding retinal tissues. The quantification of mRNA extracted from the heads of the larvae by using real-time quantitative polymerase chain reaction revealed a twofold increase in vegfaa and vegfr2 expression compared with the control group, indicating increased vascular endothelial growth factor signaling in the hypoxic condition. In addition, we demonstrated that the hypoxic insult could be effectively rescued by several antivascular endothelial growth factor agents such as SU5416, bevacizumab, and ranibizumab. In conclusion, we provide a simple, highly reproducible, and clinically relevant retinopathy of prematurity model based on zebrafish embryos; this model may serve as a useful platform for clarifying the mechanisms of human retinopathy of prematurity and its progression.
Highlights
Retinopathy of prematurity (ROP), formerly known as retrolental fibroplasia [1], is one of the most common causes of infantile blindness [2] and is characterized by a vasoproliferative and PLOS ONE | DOI:10.1371/journal.pone.0126750 May 15, 2015A Zebrafish Model of Retinopathy of Prematurity fibrotic change in the vitreous body and retina [3]
A quantitative real-time RT-PCR (qRT-PCR) study was performed to quantify the mRNA levels of vegfaa and vegfr2 and, confirm that CoCl2 induces hypoxia
Overexpression of vegfaa and vegfr2 mRNA is consistent with hypoxia, indicating that CoCl2-induced hypoxia in zebrafish is suitable for ROP disease modeling
Summary
A Zebrafish Model of Retinopathy of Prematurity fibrotic change in the vitreous body and retina [3]. In the Early Treatment for Retinopathy of Prematurity Study in the United States, the incidence of ROP among infants with a birth weight of less than 1251g was 68% and increased as the birth weight decreased [4]. In ROP, prematurity leads to incomplete retinal vascularization in the early gestational age. The avascularized retina in ROP becomes increasingly hypoxic with metabolic activity and growth. This leads to the second chronic phase of ROP, which involves rapid neovascularization with hypoxia and the expression of hypoxia-inducible transcription factor (HIF) and vascular endothelial growth factor (VEGF) [8]. Partial and eventual total retinal detachment occur [9]
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