Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF‐1α‐VEGF pathway in oxygen‐induced retinopathy mice

Abstract

Retinopathy of prematurity (ROP) is a retinopathy characterized by retinal neovascularization (RNV) occurring in preterm infants treated with high concentrations of oxygen and may lead to blindness in severe cases. Currently, anti-VEGF therapy is a major treatment for ROP, but it is costly and may cause serious complications. The previous study has demonstrated that melatonin exerted neuroprotective effect against retinal ganglion cell death induced by hypoxia in neonatal rats. However, whether melatonin is anti-angiogenic and neuroglial protective in the progression of ROP remains unknown. Thus, this study was to investigate the effect of melatonin on RNV and neuroglia in the retina of oxygen-induced retinopathy (OIR) mice. The results showed a reduction in retinal vascular leakage in OIR mice after melatonin treatment. Besides, the size of retinal neovascular and avascular areas, the number of preretinal neovascular cell nuclei, and the number of proliferative vascular endothelial cells within the neovascular area were significantly decreased in mice treated with melatonin. After oxygen-induced injury, the density of astrocytes was decreased, accompanied by morphologic and functional changes of astrocytes. Besides, retinal microglia were also activated. Meanwhile, the levels of inflammatory factors were elevated. However, these pathologic processes were all hindered by melatonin treatment. Furthermore, HIF-1α-VEGF pathway was activated in the retina of OIR mice, yet was suppressed in melatonin-treated OIR mice retinas. In conclusion, melatonin prevented pathologic neovascularization, protected neuroglial cells, and exerts anti-inflammation effect via inhibition of HIF-1α-VEGF pathway in OIR retinas, suggesting that melatonin could be a promising therapeutic agent for ROP.

Landscape of microRNA in the aqueous humour of proliferative diabetic retinopathy as assessed by next‐generation sequencing

“…All animal studies were approved by the Institutional Animal Care and Use Committee of Zhongshan Ophthalmic Center and adherence to the ARVO Animal Statement. Oxygen‐induced retinopathy (OIR) was generated as previously described . Neonatal mice and their nursing mother were exposed to 75% oxygen from P7‐12 to induce retinopathy, and the mice were killed at P17.…”

“…Oxygeninduced retinopathy (OIR) was generated as previously described. 21 Neonatal mice and their nursing mother were exposed to 75% oxygen from P7-12 to induce retinopathy, and the mice were killed at P17. The retinas of the neonatal mice were collected, and the total RNA including miRNA of the entire retinas was extracted using the miRNeasy Mini kit (Qiagen, Hilden, Germany).…”

“…miRNAs constitute a large family of small (19)(20)(21)(22) nucleotides long), non-coding RNAs that act as post-transcriptional regulators of gene expression. 6 Due to their stability in biofluids such as blood, urine, and aqueous humour (AH), 7 as well as their cell-type and tissue specificity, miRNAs are potential biomarkers for the detection of DR. 4 A few studies have detected miRNAs in the blood or vitreous humour of DR patients using microarray or polymerase chain reaction (PCR), and suggested that miRNA may be involved in DR and that some miRNAs may be biomarkers for DR. [8][9][10][11][12][13] However, miRNA arrays or PCR have only been able to detect some of the mature miRNAs in the known miRbase database.…”

MicroRNA-18a-5p Administration Suppresses Retinal Neovascularization by Targeting FGF1 and HIF1A

“…Laser photocoagulation, the standard treatment for proliferative retinopathy, has a high rate of visual and anatomic success (Wallace and Wu, 2013). Anti-VEGF drugs are widely used as the major treatment in both ROP and DR to achieve certain efficacy (Xu et al, 2018). However, 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).…”

“…Anti-VEGF drugs are widely used as the major treatment in both ROP and DR to achieve certain efficacy (Xu et al, 2018). However, 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). Therefore, it is critical to explore and identify additional factors that regulate pathological neovascularization in order to exploit new therapeutic drugs.…”