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Updated: Feb 6, 2026
Author Spotlight: Understanding Retinal Vessel Resilience and Disease Progression
Published on: January 12, 2024
Adenosine A2A receptor antagonists act at the hyperoxic phase to confer protection against retinopathy
Rong Zhou1,2, Shuya Zhang1,2, Xuejiao Gu1,2
1Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, 325027, Zhejiang, China.
Insights
Adenosine A2A receptor antagonists offer a novel therapeutic strategy for retinopathy of prematurity. This study found that KW6002 effectively reduced pathological neovascularization during the hyperoxic phase in an OIR mouse model.
Area of Science:
- Ophthalmology
- Pharmacology
- Developmental Biology
Background:
- Retinopathy of prematurity (ROP) is a leading cause of childhood blindness.
- Current treatments like laser photocoagulation and anti-VEGF antibodies have limitations, including reduced peripheral vision and impaired retinal development.
- Adenosine A2A receptor (A2AR) antagonists are explored as a novel therapeutic approach for ROP.
Purpose of the Study:
- To investigate the therapeutic potential of adenosine A2A receptor (A2AR) antagonists in controlling pathological retinal neovascularization.
- To evaluate the efficacy of A2AR antagonist KW6002 in an oxygen-induced retinopathy (OIR) mouse model of ROP.
- To determine the optimal treatment window for A2AR antagonist intervention in ROP.
Main Methods:
- C57BL/6 mice were subjected to oxygen-induced retinopathy (OIR) model.
- KW6002 or vehicle was administered at different postnatal developmental stages.
- Retinal vascularization, cellular proliferation, apoptosis, astrocyte and microglial activation, and tip cell function were assessed using various staining and molecular techniques.
- Statistical analysis was performed using ANOVA and t-tests.
Main Results:
- KW6002 treatment during the hyperoxic phase (P7-P12) significantly reduced avascular areas and pathological neovascularization in OIR mice.
- Treatment did not impede normal retinal vascular development.
- KW6002 administration led to reduced cellular apoptosis and proliferation, and enhanced astrocyte and tip cell functions.
- The antagonist was most effective when administered during the hyperoxic phase, not the predicted hypoxic phase.
Conclusions:
- The hyperoxic phase represents a critical therapeutic window for ROP treatment.
- A2AR antagonists selectively reduce pathological angiogenesis without affecting physiological vascularization.
- A2AR antagonists demonstrate significant therapeutic potential as a novel strategy for ROP treatment.
Background:
Retinopathy of prematurity (ROP) remains a major cause of childhood blindness and current laser photocoagulation and anti-VEGF antibody treatments are associated with reduced peripheral vision and possible delayed development of retinal vasculatures and neurons. In this study, we advanced the translational potential of adenosine A2A receptor (A2AR) antagonists as a novel therapeutic strategy for selectively controlling pathological retinal neovascularization in oxygen-induced retinopathy (OIR) model of ROP.
Methods:
Developing C57BL/6 mice were exposed to 75% oxygen from postnatal (P) day 7 to P12 and to room air from P12 to P17 and treated with KW6002 or vehicle at different postnatal developmental stages. Retinal vascularization was examined by whole-mount fluorescence and cross-sectional hematoxylin-eosin staining. Cellular proliferation, astrocyte and microglial activation, and tip cell function were investigated by isolectin staining and immunohistochemistry. Apoptosis was analyzed by TUNEL assay. The effects of oxygen exposure and KW6002 treatment were analyzed by two-way ANOVA or Kruskal-Wallis test or independent Student's t-test or Mann-Whitney U test.
Results:
The A2AR antagonist KW6002 (P7-P17) did not affect normal postnatal development of retinal vasculature, but selectively reduced avascular areas and neovascularization, with the reduced cellular apoptosis and proliferation, and enhanced astrocyte and tip cell functions in OIR. Importantly, contrary to our prediction that A2AR antagonists were most effective at the hypoxic phase with aberrantly increased adenosine-A2AR signaling, we discovered that the A2AR antagonist KW6002 mainly acted at the hyperoxic phase to confer protection against OIR as KW6002 treatment at P7-P12 (but not P12-P17) conferred protection against OIR; this protection was observed as early as P9 with reduced avascular areas and reduced cellular apoptosis and reversal of eNOS mRNA down-regulation in retina of OIR.
Conclusions:
As ROP being a biphasic disease, our identification of the hyperoxic phase as the effective window, together with selective and robust protection against pathological (but not physiological) angiogenesis, elevates A2AR antagonists as a novel therapeutic strategy for ROP treatment.
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