TY - JOUR
T1 - Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis
AU - Liu, Zhiping
AU - Yan, Siyuan
AU - Wang, Jiaojiao
AU - Xu, Yiming
AU - Wang, Yong
AU - Zhang, Shuya
AU - Xu, Xizhen
AU - Yang, Qiuhua
AU - Zeng, Xianqiu
AU - Zhou, Yaqi
AU - Gu, Xuejiao
AU - Lu, Sarah
AU - Fu, Zhongjie
AU - Fulton, David J
AU - Weintraub, Neal Lee
AU - Caldwell, Ruth B
AU - Zhang, Wenbo
AU - Wu, Chaodong
AU - Liu, Xiao Ling
AU - Chen, Jiang Fan
AU - Ahmad, Aftab
AU - Kaddour-Djebbar, Ismail
AU - Al-Shabrawey, Mohamed
AU - Li, Qinkai
AU - Jiang, Xuejun
AU - Sun, Ye
AU - Sodhi, Akrit
AU - Smith, Lois
AU - Hong, Mei
AU - Huo, Yuqing
N1 - Funding Information:
We appreciate Yan V. Sun (Department of Epidemiology, Rollins School of Public Health, Emory University), and Hongyan Xu (Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University) for collecting data from http://www.gtexportal.org/home. This work was supported by grants from National Key Basic Research Program of China (2012CB910402), National Natural Science Foundation of China (81400826), Guangdong Natural Science Foundation (2014A030312004), the Shenzhen Science and Technology Innovation Committee (20160517084712652, 20160503001803075, JCYJ20140903101709818, JSGG20140717102922014), the Shenzhen Peacock Program (KQCX2015032709315529), American Heart Association (16GRNT30510010), and the National Institutes of Health (HL095556, R01DK095862).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-017-00551-2
DO - 10.1038/s41467-017-00551-2
M3 - Article
C2 - 28928465
AN - SCOPUS:85029871575
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 584
ER -
