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Targeting adenosine A2A receptors for early intervention of retinopathy of prematurity

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Abstract

Retinopathy of prematurity (ROP) continues to pose a significant threat to the vision of numerous children worldwide, primarily owing to the increased survival rates of premature infants. The pathologies of ROP are mainly linked to impaired vascularization as a result of hyperoxia, leading to subsequent neovascularization. Existing treatments, including anti-vascular endothelial growth factor (VEGF) therapies, have thus far been limited to addressing pathological angiogenesis at advanced ROP stages, inevitably leading to adverse side effects. Intervention to promote physiological angiogenesis during the initial stages could hold the potential to prevent ROP. Adenosine A2A receptors (A2AR) have been identified in various ocular cell types, exhibiting distinct densities and functionally intricate connections with oxygen metabolism. In this review, we discuss experimental evidence that strongly underscores the pivotal role of A2AR in ROP. In particular, A2AR blockade may represent an effective treatment strategy, mitigating retinal vascular loss by reversing hyperoxia-mediated cellular proliferation inhibition and curtailing hypoxia-mediated neovascularization in oxygen-induced retinopathy (OIR). These effects stem from the interplay of endothelium, neuronal and glial cells, and novel molecular pathways (notably promoting TGF-β signaling) at the hyperoxia phase. We propose that pharmacological targeting of A2AR signaling may confer an early intervention for ROP with distinct therapeutic benefits and mechanisms than the anti-VEGF therapy.

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Acknowledgements

We are grateful to Sijia Ling for her excellent schematic illustration in this review. We also thank Dr. Xiaoxin Chen (University of Waterloo, Canada) for editing and proofreading the manuscript.

Funding

This study was funded by the National Natural Science Foundation of China (Grant #82151308 to J.-F.C.; 82101556 to X.Z.), the Research Fund for International Senior Scientists (Grant #82150710558 to J.-F.C), Start-up Fund (Grant #OJQDSP2022007 to J.-F.C.) from the Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Pro-gram Project from the State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University (Grant #J01-20190101 to J.-F.C), Key Research Project (Grant #2023C03079 to J.-F.C) from Zhejiang Provincial Administration of Science & Technology, and the Natural Science Foundation of Zhejiang Province of China (Grant #LQ22H090013 to X.Z).

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  1. The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China

    Xuhao Chen, Xiaoting Sun, Yuanyuan Ge, Xuzhao Zhou & Jiang-Fan Chen

  2. Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, China

    Jiang-Fan Chen

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Xuhao Chen, Xiaoting Sun, and YuanYuan Ge collected materials and wrote the manuscript. Xuzhao Zhou and Jiang-fan Chen are responsible for critical revisions of the article. Funds of this article are supported by Xuzhao Zhou and Jiang-fan Chen. All authors revised and agreed on the final version of the manuscript.

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Chen, X., Sun, X., Ge, Y. et al. Targeting adenosine A2A receptors for early intervention of retinopathy of prematurity. Purinergic Signalling (2024). https://doi.org/10.1007/s11302-024-09986-x

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