Retinopathy of prematurity (ROP) remains one of the major causes of blindness in children worldwide. While current ROP treatments are mostly disruptive to reduce proliferative neovascularization by targeting the hypoxic phase, protection against early hyperoxia-induced retinal vascular loss represents an effective therapeutic window, but no such therapeutic strategy is available. Built upon our recent demonstration that the protection against oxygen-induced retinopathy by adenosine A_2A receptor (A_2AR) antagonists is most effective when administered at the hyperoxia (not hypoxic) phase, we here uncovered the cellular mechanism underlying the A_2AR-mediated protection against early hyperoxia-induced retinal vascular loss by reversing the inhibition of cellular proliferation via possibly multiple signaling pathways. Specifically, we revealed two distinct stages of the hyperoxia phase with greater cellular proliferation and apoptosis activities and upregulation of adenosine signaling at postnatal 9 day (P9) but reduced cellular activities and adenosine-A_2AR signaling at P12. Importantly, the A_2AR-mediated protection at P9 was associated with the reversal of hyperoxia-induced inhibition of progenitor cells at the peripheral retina at P9 and of retinal endothelial proliferation at P9 and P12. The critical role of cellular proliferation in the hyperoxia-induced retinal vascular loss was validated by the increased avascular areas by siRNA knockdown of the multiple signaling molecules involved in modulation of cellular proliferation, including activin receptor-like kinase 1, DNA-binding protein inhibitor 1, and vascular endothelial growth factor-A.

中文翻译：

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腺苷 A2A 受体拮抗作用通过细胞增殖防止高氧诱导的视网膜血管损失

早产儿视网膜病变 (ROP) 仍然是全球儿童失明的主要原因之一。虽然目前的 ROP 治疗主要是通过靶向缺氧阶段来减少增殖性新血管形成，但防止早期高氧诱导的视网膜血管损失是一个有效的治疗窗口，但没有这样的治疗策略可用。基于我们最近的证明，腺苷 A _2A受体（A _2A R）拮抗剂在高氧（非缺氧）期给药时对氧诱导的视网膜病变的保护最有效，我们在这里揭示了 A _2A的细胞机制R 介导的对早期高氧诱导的视网膜血管损失的保护，通过可能通过多种信号通路逆转细胞增殖的抑制。具体而言，我们揭示了高氧期的两个不同阶段，在出生后第 9 天（P9）具有更大的细胞增殖和凋亡活性以及腺苷信号传导的上调，但在 P12 时细胞活性和腺苷-A _2A R 信号传导降低。重要的是，A _2AR 介导的 P9 保护与高氧诱导的 P9 外周视网膜祖细胞抑制和 P9 和 P12 视网膜内皮增殖的逆转有关。细胞增殖在高氧诱导的视网膜血管损失中的关键作用通过 siRNA 敲低参与调节细胞增殖的多种信号分子（包括激活素受体样激酶 1、DNA 结合蛋白抑制剂 1）增加的无血管区域来验证和血管内皮生长因子-A。