Adenosine A(1) Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms

作者：Zhang, Shuya; Li, Haiyan; Li, Bo; Zhong, Dingjuan; Gu, Xuejiao; Tang, Lingyun; Wang, Yanyan; Wang, Cun; Zhou, Rong; Li, Yan; He, Yan; Chen, Mozi; Huo, Yuqing; Liu, Xiao-Ling; Chen, Jiang-Fan^*

来源：Investigative Ophthalmology & Visual Science, 2015, 56(13): 8108-8119.

DOI：10.1167/iovs.15-17202

• adenosine A(1) receptor
• oxygen-induced retinopathy
• proliferative retinopathy
• retinal revascularization
• neovascularization
• endothelial tip cells
• vaso-obliteration

PURPOSE. We critically evaluated the role of the adenosine A(1) receptor (A(1)R) 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 A(1)Rs 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 vasoobliterative 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.

• 出版日期2015-12
• 单位温州医科大学; 北京大学深圳研究生院