Abstract
Pathologic ocular neovascularization commonly results in visual impairment or even blindness in numerous fundus diseases, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and age-related macular degeneration (AMD). MicroRNAs regulate angiogenesis through modulating target genes and disease progression, making them a new class of targets for drug discovery. In this study, we investigated the potential role of miR-18a-5p in retinal neovascularization using a mouse model of oxygen-induced proliferative retinopathy (OIR). We found that miR-18a-5p was highly expressed in the retina of pups as well as retinal endothelial cells, and was consistently down-regulated during retinal development. On the other hand, miR-18a-5p was increased significantly during pathologic neovascularization in the retinas of OIR mice. Moreover, intravitreal administration of miRNA mimic, agomiR-18a-5p, significantly suppressed retinal neovascularization in OIR models. Accordingly, agomir-18a-5p markedly suppressed human retinal microvascular endothelial cell (HRMEC) function including proliferation, migration, and tube formation ability. Additionally, we demonstrated that miR-18a-5p directly down-regulated known vascular growth factors, fibroblast growth factor 1 (FGF1) and hypoxia-inducible factor 1-alpha (HIF1A), as the target genes. In conclusion, miR-18a-5p may be a useful drug target for pathologic ocular neovascularization.
Highlights
The intraretinal vasculature supplies the inner part of the retina with oxygen and nutrients (Fruttiger, 2007)
We investigated the effects of miR-18a-5p on the human retinal microvascular endothelial cell (HRMEC) function and oxygen-induced proliferative retinopathy (OIR) models to elucidate the participation of miR-18a-5p in the initiation and progression of ocular neovascularization
To identify miRNAs that are regulated in developing retina, total RNAs isolated from pups retina at postnatal day 1 (P1), postnatal day 7 (P7), and P17, and performed high-throughput sequencing (GEO accession No GSE142029)
Summary
The intraretinal vasculature supplies the inner part of the retina with oxygen and nutrients (Fruttiger, 2007). Dysfunctional angiogenesis is involved in many diseases, including cardiovascular diseases, tumorigenesis, and proliferative retinopathies (Folkman, 1995). Proliferative retinopathies such as proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and retina vein occlusion (RVO) are characterized by pathological retinal neovascularization, which is the leading cause of blindness (Augustin and Koh, 2017). Anti-VEGF drugs are widely used as the major treatment in both ROP and DR to achieve certain efficacy (Xu et al, 2018) Despite these considerable advances, an increasing number of clinical studies have reported that laser treatment and anti-VEGF therapy does have some limitations and causes undesirable side effects (Potente et al, 2011; Xu et al, 2018). It is critical to explore and identify additional factors that regulate pathological neovascularization in order to exploit new therapeutic drugs
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