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Updated: Jan 27, 2026

Oxygen-Induced Retinopathy Model for Ischemic Retinal Diseases in Rodents
Published on: September 16, 2020
Pharmacological HIF inhibition prevents retinal neovascularization with improved visual function in a murine
Yukihiro Miwa1, Yusuke Hoshino2, Chiho Shoda3
1Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Abstract:
Neovascular retinal diseases are the leading causes of blindness in advanced countries. To date, anti-VEGF (vascular endothelial growth factor) drugs are clinically effective and widely used for these diseases. However, recent animal and clinical studies reported that potent and long-term VEGF antagonism may induce chorioretinal atrophy. Thus, physiological amount of VEGF is required for the homeostasis in the retina. Hypoxia-inducible factors (HIFs) are transcription factors located upstream of VEGF. We hypothesized that ectopically stabilized HIFs induce pathological amount of VEGF involved with retinal neovascularization. Therefore, HIF inhibition could be an alternative therapeutic candidate targeting the pathological amount of VEGF while holding a physiological amount of VEGF. To test this hypothesis, topotecan and doxorubicin, HIF inhibitors with different mechanisms were administered to the murine oxygen-induced retinopathy (OIR) model. We found that both topotecan and doxorubicin significantly prevented pathological but not physiological neovascularization in OIR. Furthermore, impaired visual function observed in OIR can also be suppressed by administering topotecan. These data suggested that HIF inhibition may be effective for pathological angiogenesis and neurodegeneration of the retina.
Insights
Hypoxia-inducible factor (HIF) inhibition effectively treats pathological retinal neovascularization without harming physiological levels. This approach may offer a new therapy for blindness-causing retinal diseases and associated vision loss.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Neovascular retinal diseases are a primary cause of blindness globally.
- Anti-vascular endothelial growth factor (VEGF) therapies are effective but can cause chorioretinal atrophy.
- Physiological VEGF levels are crucial for retinal homeostasis.
Purpose of the Study:
- To investigate if inhibiting hypoxia-inducible factors (HIFs) can target pathological VEGF levels while preserving physiological amounts.
- To explore HIF inhibition as an alternative therapeutic strategy for neovascular retinal diseases.
Main Methods:
- Utilized the murine oxygen-induced retinopathy (OIR) model.
- Administered topotecan and doxorubicin, known HIF inhibitors with distinct mechanisms.
- Assessed the effects on pathological and physiological neovascularization and visual function.
Main Results:
- Both topotecan and doxorubicin significantly inhibited pathological neovascularization in OIR.
- Neither drug affected physiological neovascularization.
- Topotecan administration improved visual function in OIR models.
Conclusions:
- HIF inhibition is a promising therapeutic strategy for pathological retinal angiogenesis.
- Targeting HIFs may offer a way to treat retinal neovascularization and neurodegeneration while maintaining essential VEGF functions.
- This approach could lead to novel treatments for blindness-causing retinal conditions.
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