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Background <p>Anti-angiogenic therapies, which suppress pathological vessel growth in neovascular diseases such as diabetic retinopathy and neovascular age-related macular degeneration (nAMD), have transformed the clinical landscape. However, a critical unmet challenge is to shift the therapeutic paradigm from broad inhibition towards achieving vascular normalization, as non-selective angiogenic blockade can result in detrimental off-target effects. Consequently, the identification of novel molecular targets is imperative for developing more precise and effective treatment strategies.</p> Methods <p>We evaluated CDH13 expression in fibrovascular membranes (FVMs) and nAMD derived from human using bioinformatics analysis and confirmed its presence in mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) via western blot, RT-PCR, and immunostaining. We then investigated CDH13 function through in vitro transwell, wound healing, and EdU assays following its knockdown, and extended our analysis in vivo using isolectin B4 staining, fundus fluorescein angiography, and immunofluorescent staining in mice subjected to <i>CDH13</i> knockdown or treated with the oral inhibitor GW3965. Finally, we employed dual-luciferase reporter assays, RT-PCR, and western blot to elucidate the underlying molecular mechanisms.</p> Results <p>We observed substantial CDH13 expression in endothelial cells of human nAMD fibrovascular membranes and mouse models of OIR and CNV. <i>CDH13</i> knockdown inhibited pathological vessel growth, promoted vascular normalization, and induced a pro-regenerative environment. Mechanistically, hypoxia inhibits NR2F2, thereby de-repressing <i>CDH13</i> transcription and activating the NF-κB pathway to drive vascular dysfunction. Additionally, oral GW3965 treatment reduced LDL deposition and alleviated pathological neovascularization through LXR activation, countering CDH13-mediated effects.</p> Conclusion <p>Together, these findings establish CDH13 as a promising therapeutic target for driving vascular normalization in neovascular retinal diseases.</p> Graphical Abstract <p></p>

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Targeting CDH13 as a therapeutic strategy to mitigate pathological ocular angiogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Wenjie Yin,
  • Miao Xu,
  • Zixuan Niu,
  • Yan Gao,
  • Na Su,
  • Yutong Song,
  • Qinghuai Liu

摘要

Background

Anti-angiogenic therapies, which suppress pathological vessel growth in neovascular diseases such as diabetic retinopathy and neovascular age-related macular degeneration (nAMD), have transformed the clinical landscape. However, a critical unmet challenge is to shift the therapeutic paradigm from broad inhibition towards achieving vascular normalization, as non-selective angiogenic blockade can result in detrimental off-target effects. Consequently, the identification of novel molecular targets is imperative for developing more precise and effective treatment strategies.

Methods

We evaluated CDH13 expression in fibrovascular membranes (FVMs) and nAMD derived from human using bioinformatics analysis and confirmed its presence in mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) via western blot, RT-PCR, and immunostaining. We then investigated CDH13 function through in vitro transwell, wound healing, and EdU assays following its knockdown, and extended our analysis in vivo using isolectin B4 staining, fundus fluorescein angiography, and immunofluorescent staining in mice subjected to CDH13 knockdown or treated with the oral inhibitor GW3965. Finally, we employed dual-luciferase reporter assays, RT-PCR, and western blot to elucidate the underlying molecular mechanisms.

Results

We observed substantial CDH13 expression in endothelial cells of human nAMD fibrovascular membranes and mouse models of OIR and CNV. CDH13 knockdown inhibited pathological vessel growth, promoted vascular normalization, and induced a pro-regenerative environment. Mechanistically, hypoxia inhibits NR2F2, thereby de-repressing CDH13 transcription and activating the NF-κB pathway to drive vascular dysfunction. Additionally, oral GW3965 treatment reduced LDL deposition and alleviated pathological neovascularization through LXR activation, countering CDH13-mediated effects.

Conclusion

Together, these findings establish CDH13 as a promising therapeutic target for driving vascular normalization in neovascular retinal diseases.

Graphical Abstract