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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.
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1 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
2 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
3 Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
4 Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
5 Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
6 Department of Ophthalmology & Visual Sciences, University of Texas Medical Branch (UTMB), Galveston, TX, USA
7 Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA
8 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
9 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