Adenosine A1 Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms.
Adenosine A1 Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms.
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DOI：
10.1167/iovs.15-17202
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发表时间：
2015-12
影响因子：
4.4
通讯作者：
Shuya Zhang;Haiyan Li;Bo Li;Dingjuan Zhong;Xuejiao Gu;Lingyun Tang;Yanyan Wang;Cun Wang;
中科院分区：
文献类型：
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作者：
Shuya Zhang;Haiyan Li;Bo Li;Dingjuan Zhong;Xuejiao Gu;Lingyun Tang;Yanyan Wang;Cun Wang;
目的 通过使用 A1R 敲除 (KO) 小鼠和氧诱导视网膜病变 (OIR) 模型，我们严格评估了腺苷 A1 受体 (A1R) 在视网膜血管正常发育和早产儿视网膜病变 (ROP) 发病机制中的作用。方法 在正常出生后发育过程中或从出生后第 7 天到第 12 天接受 75% 氧气，从第 12 天到第 17 天接受室内空气（ROP 的 OIR 模型）后，对 A1R 缺陷的小鼠及其野生型 (WT) 同窝小鼠进行检查。通过整体荧光和横截面苏木精-伊红染色检查视网膜血管化。通过异凝集素染色和免疫组织化学测定细胞增殖、星形胶质细胞和小胶质细胞活化以及尖端细胞功能。通过TUNEL测定法测定细胞凋亡。结果 A1R 基因缺失并不影响出生后发育过程中的正常视网膜血管化，WT 和 A1R KO 小鼠视网膜中的三层血管化模式无法区分。在 OIR 模型中，A1R 的基因缺失导致了阶段特异性效应：在 P12 时减少了高氧诱导的视网膜血管闭塞，但在 P17 时减少了无血管面积并减弱了缺氧诱导的视网膜内血运重建，而不影响玻璃体内新生血管形成，在 P21 时减少了视网膜的无血管面积。 A1R 对 OIR 的这些独特作用与 A1R 主要在血管闭塞期 (P12) 控制内核和外核层的细胞凋亡以及血管增殖期 (P17) 内皮尖端细胞的生长有关，而不会改变细胞增殖、星形胶质细胞活化和组织炎症。结论 腺苷 A1 受体活性不是视网膜脉管系统出生后正常发育所必需的，但通过不同的细胞机制选择性地控制高氧诱导的血管闭塞和缺氧驱动的血运重建。
PURPOSE We critically evaluated the role of the adenosine A1 receptor (A1R) in normal development of retinal vasculature and pathogenesis of retinopathy of prematurity (ROP) by using the A1R knockout (KO) mice and oxygen-induced retinopathy (OIR) model. METHODS Mice deficient in A1Rs and their wild-type (WT) littermates were examined during normal postnatal development or after being subjected to 75% oxygen from postnatal day (P) 7 to P12 and to room air from P12 to P17 (OIR model of ROP). 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 determined by isolectin staining and immunohistochemistry. Apoptosis was determined by TUNEL assay. RESULTS Genetic deletion of the A1R did not affect normal retinal vascularization during postnatal development with indistinguishable three-layer vascularization patterns in retina between WT and A1R KO mice. In the OIR model, genetic deletion of the A1R resulted in stage-specific effects: reduced hyperoxia-induced retinal vaso-obliteration at P12, but reduced avascular area and attenuated hypoxia-induced intraretinal revascularization without affecting intravitreal neovascularization at P17 and reduced avascular areas in retina at P21. These distinct effects of A1Rs on OIR were associated with A1R control of apoptosis mainly in inner and outer nuclear layers at the vaso-obliterative phase (P12) and the growth of endothelium tip cells at the vasoproliferative phase (P17), without modification of cellular proliferation, astrocytic activation, and tissue inflammation. CONCLUSIONS Adenosine A1 receptor activity is not required for normal postnatal development of retinal vasculature but selectively controls hyperoxia-induced vaso-obliteration and hypoxia-driven revascularization by distinct cellular mechanisms.