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 ChenAftab Ahmad, Ismail Kaddour-Djebbar, Mohamed Al-Shabrawey, Qinkai Li, Xuejun Jiang, Ye Sun, Akrit Sodhi, Lois Smith, Mei Hong, Yuqing Huo

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number584
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

glycolysis
Pathologic Neovascularization
angiogenesis
adenosines
Purinergic P1 Receptors
hypoxia
Endothelial cells
Glycolysis
Endothelial Cells
enzymes
Hypoxia-Inducible Factor 1
mice
Transcription Factors
Enzymes
Chemical activation
activation
Oxygen
Cell Hypoxia
deletion
Enzyme Induction

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis. / Liu, Zhiping; Yan, Siyuan; Wang, Jiaojiao; Xu, Yiming; Wang, Yong; Zhang, Shuya; Xu, Xizhen; Yang, Qiuhua; Zeng, Xianqiu; Zhou, Yaqi; Gu, Xuejiao; Lu, Sarah; Fu, Zhongjie; Fulton, David J.; Weintraub, Neal L.; Caldwell, Ruth B.; Zhang, Wenbo; Wu, Chaodong; Liu, Xiao Ling; Chen, Jiang Fan; Ahmad, Aftab; Kaddour-Djebbar, Ismail; Al-Shabrawey, Mohamed; Li, Qinkai; Jiang, Xuejun; Sun, Ye; Sodhi, Akrit; Smith, Lois; Hong, Mei; Huo, Yuqing.

In: Nature Communications, Vol. 8, No. 1, 584, 01.12.2017.

Research output: Contribution to journalArticle

Liu, Z, Yan, S, Wang, J, Xu, Y, Wang, Y, Zhang, S, Xu, X, Yang, Q, Zeng, X, Zhou, Y, Gu, X, Lu, S, Fu, Z, Fulton, DJ, Weintraub, NL, Caldwell, RB, Zhang, W, Wu, C, Liu, XL, Chen, JF, Ahmad, A, Kaddour-Djebbar, I, Al-Shabrawey, M, Li, Q, Jiang, X, Sun, Y, Sodhi, A, Smith, L, Hong, M & Huo, Y 2017, 'Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis', Nature Communications, vol. 8, no. 1, 584. https://doi.org/10.1038/s41467-017-00551-2
Liu, Zhiping ; Yan, Siyuan ; Wang, Jiaojiao ; Xu, Yiming ; Wang, Yong ; Zhang, Shuya ; Xu, Xizhen ; Yang, Qiuhua ; Zeng, Xianqiu ; Zhou, Yaqi ; Gu, Xuejiao ; Lu, Sarah ; Fu, Zhongjie ; Fulton, David J. ; Weintraub, Neal L. ; Caldwell, Ruth B. ; Zhang, Wenbo ; Wu, Chaodong ; Liu, Xiao Ling ; Chen, Jiang Fan ; Ahmad, Aftab ; Kaddour-Djebbar, Ismail ; Al-Shabrawey, Mohamed ; Li, Qinkai ; Jiang, Xuejun ; Sun, Ye ; Sodhi, Akrit ; Smith, Lois ; Hong, Mei ; Huo, Yuqing. / Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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AU - Zhang, Shuya

AU - Xu, Xizhen

AU - Yang, Qiuhua

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AU - Gu, Xuejiao

AU - Lu, Sarah

AU - Fu, Zhongjie

AU - Fulton, David J.

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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

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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.

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