Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis

Zhiping Liu, Siyuan Yan, Jiaojiao Wang, Yiming Xu, Yong Wang, Shuya Zhang, Xizhen Xu, Qiuhua Yang, Xianqiu Zeng, Yaqi Zhou, Xuejiao Gu, Sarah Lu, Zhongjie Fu, David J. Fulton, Neal L. Weintraub, Ruth B. Caldwell, Wenbo Zhang, Chaodong Wu, Xiao-Ling Liu, Jiang-Fan Chen, Aftab Ahmad, Ismail Kaddour-Djebbar, Mohamed Al-Shabrawey, Qinkai Li, Xuejun Jiang, Ye Sun, Akrit Sodhi, Lois Smith, Mei Hong, Yuqing Huo

Adenosine/adenosine receptor-mediated signaling has been implicated in the development of various ischemic diseases, including ischemic retinopathies. Here, we show that the adenosine A2a receptor (ADORA2A) promotes hypoxia-inducible transcription factor-1 (HIF-1)-dependent endothelial cell glycolysis, which is crucial for pathological angiogenesis in proliferative retinopathies. Adora2a expression is markedly increased in the retina of mice with oxygen-induced retinopathy (OIR). Endothelial cell-specific, but not macrophage-specific Adora2a deletion decreases key glycolytic enzymes and reduces pathological neovascularization in the OIR mice. In human primary retinal microvascular endothelial cells, hypoxia induces the expression of ADORA2A by activating HIF-2α. ADORA2A knockdown decreases hypoxia-induced glycolytic enzyme expression, glycolytic flux, and endothelial cell proliferation, sprouting and tubule formation. Mechanistically, ADORA2A activation promotes the transcriptional induction of glycolytic enzymes via ERK- and Akt-dependent translational activation of HIF-1α protein. Taken together, these findings advance translation of ADORA2A as a therapeutic target in the treatment of proliferative retinopathies and other diseases dependent on pathological angiogenesis.Pathological angiogenesis in the retina is a major cause of blindness. Here the authors show that adenosine receptor A2A drives pathological angiogenesis in the oxygen-induced retinopathy mouse model by promoting glycolysis in endothelial cells via the ERK/Akt/HIF-1α pathway, thereby suggesting new therapeutic targets for disease treatment.