Genetic inactivation of the adenosine A2A receptor attenuates pathologic but not developmental angiogenesis in the mouse retina.
OBJECTIVE
The adenosine A(2A) receptor (A(2A)R) modulates normal vascularization and pathologic angiogenesis in many tissues and may contribute to the pathogenesis of retinopathy of prematurity (ROP) characterized by abnormal retinal vascularization in surviving premature infants. Here, the authors studied the effects of the genetic inactivation of A(2A)R on normal retinal vascularization and the development of pathologic angiogenesis in oxygen-induced retinopathy (OIR), an animal model of ROP.


METHODS
After exposure to 75% oxygen for 5 days (postnatal day [P] 7-P12) and subsequently to room air for the next 9 days (P13-P21), we evaluated retinal vascular morphology by ADPase staining in retinal whole mounts, retinal neovascularization response by histochemistry in serial retinal sections, and retinal VEGF gene expression by real-time PCR analysis in A(2A)R knockout (KO) mice and their wild-type (WT) littermates.


RESULTS
At P17, A(2A)R KO mice displayed attenuated OIR compared with WT littermates, as evidenced by reduced vaso-obliteration and areas of nonperfusion in the center of the retina, reduced pathologic angiogenesis as evident by decreased non-ganglion cells and neovascular nuclei, and inhibited hypoxia-induced retinal VEGF gene expression. Notably, the attenuation of pathologic angiogenesis by A(2A)R inactivation was selective for OIR because it did not affect normal retinal vascularization during postnatal development.


CONCLUSIONS
These findings provide the first evidence that A(2A)R is critical for the development of OIR and suggest a novel therapeutic approach of A(2A)R inactivation for ROP by selectively targeting pathologic but not developmental angiogenesis in the retina.
Liu
Xiao-Ling
XL
School of Optometry and Ophthalmology and Eye Hospital, Yuying Children's Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China. lxl@mail.eye.ac.cn
Zhou
Rong
R
Pan
Qi-Qi
QQ
Jia
Xiao-Lin
XL
Gao
Wei-Na
WN
Wu
Jun
J
Lin
Jing
J
Chen
Jiang-Fan
JF
D000818:Animals; D000831:Animals, Newborn; D001081:Apyrase / Q000378:metabolism; D004195:Disease Models, Animal; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010100:Oxygen / Q000633:toxicity; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics*; D012160:Retina / Q000201:enzymology; D015861:Retinal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D012171:Retinal Vessels / Q000502:physiology*; D012178:Retinopathy of Prematurity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D018809:Proliferating Cell Nuclear Antigen; D043705:Receptor, Adenosine A2A; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D001081:Apyrase; D010100:Oxygen