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      MiRNA-21-HIF-1α-VEGF Axis Is Associated with Myopic Choroidal Neovascularization in Guinea Pigs

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          Abstract

          Introduction: Myopic choroidal neovascularization (CNV) often causes serious damage to central vision. The mechanisms behind it remain unclear. Method: In this study, monocular form deprivation was applied to induce high myopia, and 532-nm laser was employed to induce CNV in guinea pig. The development of neovascularization was measured comprehensively by fundus fluorescein angiography, optical coherence tomography and hematoxylin and eosin staining. Gene expression was detected by real-time polymerase chain reaction and immunohistochemistry. Results: The proliferation of new blood vessels increased with time and peaked at 21 days. At each time point after laser photocoagulation, the incidence of CNV was higher in form-deprived myopia (FDM) group than in control group. Myopic CNV started earlier and decreased more slowly. The obvious continuous fluorescein leakage could last as long as 1 month. The expressions of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) increased and peaked at 14 days in both groups after laser photocoagulation. Moreover, after laser photocoagulation, miR-21 expression was upregulated in both groups, reached a peak at 7 days, with a level much higher in FDM group. In addition, miR-21 expression was positively correlated with VEGF and HIF-1α expression in both groups. Conclusion: miR-21 correlated with HIF-1α-VEGF signaling pathway may promote CNV formation in high-myopia guinea.

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          Optical coherence tomography

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            MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation.

            MicroRNAs (miRNAs) are a recently discovered class of endogenous, small, noncoding RNAs that regulate about 30% of the encoding genes of the human genome. However, the role of miRNAs in vascular disease is currently completely unknown. Using microarray analysis, we demonstrated for the first time that miRNAs are aberrantly expressed in the vascular walls after balloon injury. The aberrantly expressed miRNAs were further confirmed by Northern blot and quantitative real-time polymerase chain reaction. Modulating an aberrantly overexpressed miRNA, miR-21, via antisense-mediated depletion (knock-down) had a significant negative effect on neointimal lesion formation. In vitro, the expression level of miR-21 in dedifferentiated vascular smooth muscle cells was significantly higher than that in fresh isolated differentiated cells. Depletion of miR-21 resulted in decreased cell proliferation and increased cell apoptosis in a dose-dependent manner. MiR-21-mediated cellular effects were further confirmed in vivo in balloon-injured rat carotid arteries. Western blot analysis demonstrated that PTEN and Bcl-2 were involved in miR-21-mediated cellular effects. The results suggest that miRNAs are novel regulatory RNAs for neointimal lesion formation. MiRNAs may be a new therapeutic target for proliferative vascular diseases such as atherosclerosis, postangioplasty restenosis, transplantation arteriopathy, and stroke.
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              Regulation of angiogenesis by hypoxia: role of the HIF system.

              The regulation of angiogenesis by hypoxia is an important component of homeostatic mechanisms that link vascular oxygen supply to metabolic demand. Molecular characterization of angiogenic pathways, identification of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydoxylases as a family of dioxygenases that regulate HIF in accordance with oxygen availability have provided new insights into this process. Here we review these findings, and the role of HIF in developmental, adaptive and neoplastic angiogenesis. We also discuss the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2022
                October 2022
                14 February 2022
                : 65
                : 5
                : 493-505
                Affiliations
                [_a] aDepartment of Ophthalmology, Shanghai Tenth People’s Hospital, Affiliate of Tongji University, Shanghai, China
                [_b] bDepartment of Ophthalmology, Shanghai University of Medicine & Health Science Affiliated Zhou Pu Hospital, Shanghai, China
                Article
                522511 Ophthalmic Res 2022;65:493–505
                10.1159/000522511
                35158368
                ee09e0ea-001d-4a99-ad90-4b4b644b9759
                © 2022 The Author(s). Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission.

                History
                : 17 May 2021
                : 05 February 2022
                Page count
                Figures: 7, Tables: 2, Pages: 13
                Funding
                This study was supported by grants from the Natural Science Foundation of Shanghai (No. 20ZR1443600), Clinical Research Plan of SHDC (No. SHDC2020CR1043B-009), The Natural Science Foundation of Shanghai (No. 19ZR1443500), Pudong New Area Health Commission Leading Talent of Shanghai (No. PWRI2020-01), and Clinical research project of Shanghai Tenth People’s Hospital (No. SHYCS08).
                Categories
                Research Article

                Vision sciences,Ophthalmology & Optometry,Pathology
                Choroidal neovascularization,Hypoxia-inducible factor-1α,Vascular endothelial growth factor,Myopic,Guinea pig,MiR-21

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