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.

Details

Title
Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis
Author
Liu, Zhiping 1 ; Yan, Siyuan 2 ; Wang, Jiaojiao 1 ; Xu, Yiming 3   VIAFID ORCID Logo  ; Wang, Yong 3 ; Zhang, Shuya 4 ; Xu, Xizhen 3 ; Yang, Qiuhua 1 ; Zeng, Xianqiu 1 ; Zhou, Yaqi 1 ; Gu, Xuejiao 4 ; Lu, Sarah 3 ; Fu, Zhongjie 5 ; Fulton, David J 3 ; Weintraub, Neal L 3 ; Caldwell, Ruth B 3 ; Zhang, Wenbo 6 ; Wu, Chaodong 7   VIAFID ORCID Logo  ; Xiao-Ling, Liu 4 ; Jiang-Fan, Chen 8 ; Ahmad, Aftab 9 ; Ismail Kaddour-Djebbar 10 ; Al-Shabrawey, Mohamed 11 ; Li, Qinkai 12 ; Jiang, Xuejun 13 ; Sun, Ye 5   VIAFID ORCID Logo  ; Sodhi, Akrit 14 ; Smith, Lois 5 ; Hong, Mei 12 ; Huo, Yuqing 3 

 Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China; Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA 
 Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Science, Beijing, China 
 Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA 
 Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China 
 Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA 
 Department of Ophthalmology & Visual Sciences, University of Texas Medical Branch (UTMB), Galveston, TX, USA 
 Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA 
 Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China; Department of Neurology, Boston University School of Medicine, Boston, MA, USA 
 Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 
10  Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA 
11  James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, USA 
12  Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China 
13  State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Science, Beijing, China 
14  Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA 
Pages
1-18
Publication year
2017
Publication date
Sep 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1940507851
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.