Abstract
Choroidal neovascularization (CNV) is a pathological process in which aberrant blood vessels invade the subretinal space of the mammalian eye. It is a characteristic feature of the prevalent neovascular age-related macular degeneration (nAMD). Circulating microRNAs (cmiRNAs) are regarded as potentially valuable biomarkers for various age-related diseases, including nAMD. Here, we investigated cmiRNA expression in an established laser-induced CNV mouse model. Upon CNV induction in C57Bl/6 mice, blood-derived cmiRNAs were initially determined globally by RNA next generation sequencing, and the most strongly dysregulated cmiRNAs were independently replicated by quantitative reverse transcription PCR (RT-qPCR) in blood, retinal, and retinal pigment epithelium (RPE)/choroidal tissue. Our findings suggest that two miRNAs, mmu-mir-486a-5p and mmur-mir-92a-3p, are consistently dysregulated during CNV formation. Furthermore, in functional in vitro assays, a significant impact of mmu-mir-486a-5p and mmu-mir-92a-3p on murine microglial cell viability was observed, while mmu-mir-92a-3p also showed an impact on microglial mobility. Taken together, we report a robust dysregulation of two miRNAs in blood and RPE/choroid after laser-induced initiation of CNV lesions in mice, highlighting their potential role in pathology and eventual therapy of CNV-associated complications.
Highlights
The blood retinal barrier separates the neural retina from the circulatory system. It is comprised of an inner barrier, formed by tight junctions between adjacent retinal endothelial cells, and an outer network of tight junctions between adjacent retinal pigment epithelium (RPE) cells
Prior to choroidal neovascularization (CNV), the retina responds to hypoxic stress by upregulating the expression of vascular endothelial growth factor (VEGF), which in turn results in the ingrowth of new blood vessels from the choriocapillaris [1,2,3]
CNV is associated with a number of pathological conditions, including myopia and osteogenesis imperfecta, but most commonly occurs in the neovascular late-stage form of age-related macular degeneration [4,5,6]
Summary
The blood retinal barrier separates the neural retina from the circulatory system. It is comprised of an inner barrier, formed by tight junctions between adjacent retinal endothelial cells, and an outer network of tight junctions between adjacent retinal pigment epithelium (RPE) cells. The two barriers constitute a sophisticated system to allow the diffusion of very small molecules such as oxygen and glucose to the neural retina, while inhibiting the passive flux of larger particles. Pathological processes, such as choroidal neovascularization (CNV), disrupt this barrier with detrimental consequences for retinal homeostasis. Prior to CNV, the retina responds to hypoxic stress by upregulating the expression of vascular endothelial growth factor (VEGF), which in turn results in the ingrowth of new blood vessels from the choriocapillaris [1,2,3] Such fragile vessels invade the RPE monolayer, leaking serous fluid, lipids, and blood into the neural retina. CNV is associated with a number of pathological conditions, including myopia and osteogenesis imperfecta, but most commonly occurs in the neovascular late-stage form of age-related macular degeneration (nAMD) [4,5,6]
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