Abstract
Purpose:
Retinopathy of prematurity (ROP) is a major cause of childhood blindness. It is a biphasic disease characterized by initial cessation of vaso-obliteration (VO) in the retina, followed by hypoxia-induced pathologic neovascularization (NV). Due to the invasive nature and partial efficacy, current clinical treatment of ROP is less than desirable. MicroRNAs (miRNA) are a group of small non-coding RNAs involve in post-transcriptional gene regulation. There is evidence that miRNAs play critical roles in both vascular and neuronal development of retina, as well as in pathologic angiogenesis. Here we investigate whether specific miRNAs through post-transcriptional control of target genes may affect retinal vascular growth in ROP and provide new potential treatment options.
Methods:
We used oxygen-induced retinopathy (OIR) as a mouse model of ROP. Microarray was performed to identify miRNAs that are significantly altered in postnatal day (P)17 OIR retinas compared with normoxic controls, followed by RT-PCR for confirmation. Retinal neuronal and vascular layers were isolated with laser capture microdissection (LCM), and analyzed localization of miRNAs by RT-PCR. MiR-150 knockout (miR-150-/-) and wild type (WT) mice were exposed to OIR, and at P17 retinal wholemounts were stained with lectin to visualize vessels as well as quantification of total areas of VO and pathologic NV. Moreover, miR-150 mimic and negative control miRNA mimic were injected intravitreally to WT eyes with OIR at P12, with VO and NV characterized at P17.
Results:
At P17, the expression of miR-150 was significantly suppressed up to 5 fold in OIR retinas compared with normoxic controls. MiR-150 was found almost exclusively in LCM isolated retinal blood vessels, and the endothelial miR-150 levels were significantly suppressed in OIR. MiR150-/- mice in OIR showed a trend of increased retinal NV compared with WT controls. Intravitreal injection of miR-150 mimic in WT OIR eyes showed significantly decreased NV compared to contralateral eyes injected with negative control miRNA (3.57±1.00% in control, 1.37±0.34% in miR-150 mimic injection, n=5 per group, p ≤ 0.05).
Conclusions:
Our findings indicate that miR-150, expressed mainly in blood vessels in the retina, plays an important role in suppressing retinal NV in the mouse model of ROP. Mir-150 may serve as a valuable target for the development of potential treatments for ROP.
Keywords: 706 retinopathy of prematurity •
533 gene/expression •
609 neovascularization