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 () and Yuqing Huo ()
Additional contact information
Zhiping Liu: Peking University Shenzhen Graduate School
Siyuan Yan: Augusta University
Jiaojiao Wang: Peking University Shenzhen Graduate School
Yiming Xu: Augusta University
Yong Wang: Augusta University
Shuya Zhang: Wenzhou Medical University
Xizhen Xu: Augusta University
Qiuhua Yang: Peking University Shenzhen Graduate School
Xianqiu Zeng: Peking University Shenzhen Graduate School
Yaqi Zhou: Peking University Shenzhen Graduate School
Xuejiao Gu: Wenzhou Medical University
Sarah Lu: Augusta University
Zhongjie Fu: Harvard Medical School
David J. Fulton: Augusta University
Neal L. Weintraub: Augusta University
Ruth B. Caldwell: Augusta University
Wenbo Zhang: University of Texas Medical Branch (UTMB)
Chaodong Wu: Texas A&M University
Xiao-Ling Liu: Wenzhou Medical University
Jiang-Fan Chen: Wenzhou Medical University
Aftab Ahmad: University of Alabama at Birmingham
Ismail Kaddour-Djebbar: Augusta University
Mohamed Al-Shabrawey: Augusta University
Qinkai Li: Peking University Shenzhen Graduate School
Xuejun Jiang: Institute of Microbiology, Chinese Academy of Science
Ye Sun: Harvard Medical School
Akrit Sodhi: Johns Hopkins School of Medicine
Lois Smith: Harvard Medical School
Mei Hong: Peking University Shenzhen Graduate School
Yuqing Huo: Augusta University

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00551-2

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