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EMBO Mol Med. 2017 Sep;9(9):1263-1278. doi: 10.15252/emmm.201607066.

Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis.

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Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA.
College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Science, Beijing, China.
Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
Georgia Prevention Institute, Augusta University, Augusta, GA, USA.
Departments of Medical Laboratory, Imaging & Radiologic Sciences, and Neurology, Augusta University, Augusta, GA, USA.
Robert S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR, USA.
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA.


The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine-metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the levels of intracellular adenosine in human endothelial cells. Knockdown (KD) of ADK elevated intracellular adenosine, promoted proliferation, migration, and angiogenic sprouting in human endothelial cells. Additionally, mice deficient in endothelial ADK displayed increased angiogenesis as evidenced by the rapid development of the retinal and hindbrain vasculature, increased healing of skin wounds, and prompt recovery of arterial blood flow in the ischemic hindlimb. Mechanistically, hypomethylation of the promoters of a series of pro-angiogenic genes, especially for VEGFR2 in ADK KD cells, was demonstrated by the Infinium methylation assay. Methylation-specific PCR, bisulfite sequencing, and methylated DNA immunoprecipitation further confirmed hypomethylation in the promoter region of VEGFR2 in ADK-deficient endothelial cells. Accordingly, loss or inactivation of ADK increased VEGFR2 expression and signaling in endothelial cells. Based on these findings, we propose that ADK downregulation-induced elevation of intracellular adenosine levels in endothelial cells in the setting of hypoxia is one of the crucial intrinsic mechanisms that promote angiogenesis.


DNA methylation; adenosine; adenosine kinase; angiogenesis; endothelial cells

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