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other·ophthalmology, retina, preclinical research, biomedical research·PMC10866157

5-Aza-2′-Deoxycytidine Ameliorates Choroidal Neovascularization by Inhibiting the Wnt/β-Catenin Signaling Pathway

Investigative Ophthalmology & Visual Science · 10 authors, 3 centres

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Systemic administration of 5-aza-dC in mice reduced CNV area, blood flow density and intensity, and vascular leakage, as measured by optical coherence tomography angiography and fundus fluorescein angiography.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10866157

5-Aza-2′-Deoxycytidine Ameliorates Choroidal Neovascularization by Inhibiting the Wnt/β-Catenin Signaling Pathway

Investigative Ophthalmology & Visual Science

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ABSTRACT

Purpose Choroidal neovascularization (CNV) can constitute the final pathology of many ocular diseases and result in severe vision loss. Studies have demonstrated that DNA methylation is critical in retinal development, aging, and disorders. The current work investigated the effects and underlying mechanism of 5-Aza-2′-deoxycytidine (5-aza-dC), a suppressor of DNA methylation, in the pathological progression of CNV. Methods The DNA methylation profiles of retinal pigment epithelial (RPE)/choroidal complexes in normal and laser-induced CNV mice were assessed by Arraystar Mouse RefSeq Promoter Arrays. The CNV area and blood flow density and intensity were observed by optical coherence tomography angiography, and fluorescence leakage was examined by fundus fluorescein angiography in CNV mice with systemic administration of 5-aza-dC. The effects of 5-aza-dC on the biological functions of bEnd.3 cells were estimated by related assays. Notum gene promoter methylation was measured using bisulfite sequencing PCR. Methyltransferases and Wnt signaling-related genes were detected in animal and cell culture experiments by real-time PCR and immunoblot. Results Methyltransferases were upregulated, but Notum (a secretion inhibitor of Wnt signaling) was downregulated in the RPE/choroidal complexes of mice with experimental CNV. Intraperitoneal injection of 5-aza-dC inactivated the Wnt pathway and ameliorated the lesion area and the intensity and density of blood flow, as well as the degree of leakage in CNV. In vitro, vascular endothelial growth factor A (VEGFA) stimulation promoted methyltransferases expression and suppressed Notum expression, consequently activating Wnt signaling, whereas exogenous 5-aza-dC reversed VEGFA-induced hyperpermeability, proliferation, migration, and tube formation in bEnd.3 cells via demethylation of Notum promoter. Conclusions We observed that 5-aza-dC attenuates the growth of CNV by inhibiting the Wnt signaling pathway via promoter demethylation of the Wnt antagonist Notum. These findings provide a theoretical basis for methylation-based treatment with the Notum gene as a potential target for CNV treatment.

CITATION EXPORT

Xinyuan Wu, Xi Yang, Xiaochan Dai et al.. 5-Aza-2′-Deoxycytidine Ameliorates Choroidal Neovascularization by Inhibiting the Wnt/β-Catenin Signaling Pathway. Investigative Ophthalmology & Visual Science. (2024). https://doi.org/10.1167/iovs.65.2.23

AUTHORS

10 · 3 CENTRES

Xinyuan Wu, Xi Yang, Xiaochan Dai, Xiuping Chen, Minqian Shen, Jinhui Dai, Fei Yuan, Liyang Wang, Yuanzhi Yuan, Yifan Feng

1Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, China
2Department of Ophthalmology, Shanghai Geriatric Medical Center, Shanghai, China
3Department of Ophthalmology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China