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Disruption of CD73-Derived and Equilibrative Nucleoside Transporter 1–Mediated Adenosine Signaling Exacerbates Oxygen-Induced Retinopathy

  • Shuya Zhang
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Bo Li
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Lingyun Tang
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Mengyun Tong
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Nan Jiang
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Xuejiao Gu
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Yu Zhang
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Yuanyuan Ge
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Xiao-Ling Liu
    Affiliations
    State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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  • Jiang-Fan Chen
    Correspondence
    Address correspondence to Jiang-Fan Chen, State Key Laboratory of Optometry, School of Optometry and Ophthalmology, Wenzhou Medical University, 270 Xueyuan Rd., Wenzhou, Zhejiang, China.
    Affiliations
    The Oujiang Laboratory, State Key Laboratory of Optometry, Ophthalmology and Vision Science, The Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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      Retinopathy of prematurity (ROP) is characterized by pathologic angiogenesis in retina, and it remains a leading cause of blindness in children. Although enhanced extracellular adenosine is markedly increased in response to retinal hypoxia, adenosine acting at the A1 and A2A receptors oppositely affects pathologic angiogenesis. In the oxygen-induced retinopathy (OIR) model of ROP, we demonstrated herein that pharmacologic and genetic inactivation of CD73 (the key 5′-ectonucleotidase for extracellular generation of adenosine) did not affect normal retinal vasculature development but exacerbated intravitreal neovascularization at postnatal day (P) 17 and delayed revascularization at P21 of OIR. This exacerbated damage to retinal vessels by CD73 inactivation was associated with increased cellular apoptosis and microglial activation but decreased astrocyte function at P17 of OIR. Furthermore, pharmacologic blockade of equilibrative nucleoside transporter 1/2 (ENT1/2; bidirectional transport for controlling the balance of intracellular and extracellular adenosine) by 6-nitrobenzylthioinosine aggravated pathologic angiogenesis at P17 of OIR. Last, pharmacologic blockade of ENT1/2 and genetic inactivation of CD73 also aggravated avascular areas at the hyperoxia phase (P12) of OIR. Thus, disruption of CD73-derived extracellular adenosine or ENT1/2-mediated transport of adenosine flux across membrane aggravated the damage to retinal vessels. These findings support that adenosine is an endogenous protective regulator that limits oxygen-induced retinopathy, and enhancing extracellular adenosine signaling represents a novel neuroprotection strategy for ROP by targeting CD73 and ENT1/2 activities.
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