Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis

Yiming Xu, Yong Wang, Siyuan Yan, Yaqi Zhou, Qiuhua Yang, Yue Pan, Xianqiu Zeng, Xiaofei An, Zhiping Liu, Lina Wang, Jiean Xu, Yapeng Cao, David J Fulton, Neal Lee Weintraub, Zsolt Bagi, MD Nasrul Hoda, Xiaoling Wang, Qinkai Li, Mei Hong, Xuejun Jiang & 4 others Detlev Boison, Christian Weber, Chaodong Wu, Yuqing Huo

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1263-1278
Number of pages16
JournalEMBO Molecular Medicine
Volume9
Issue number9
DOIs
StatePublished - Sep 1 2017

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Adenosine Kinase
Epigenomics
Adenosine
Endothelial Cells
Methylation
Rhombencephalon
Hindlimb
DNA Sequence Analysis
Nucleosides
Immunoprecipitation
Genetic Promoter Regions
Wound Healing
Blood Vessels
Homeostasis
Down-Regulation
Polymerase Chain Reaction
Skin

Keywords

  • DNA methylation
  • adenosine
  • adenosine kinase
  • angiogenesis
  • endothelial cells

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis. / Xu, Yiming; Wang, Yong; Yan, Siyuan; Zhou, Yaqi; Yang, Qiuhua; Pan, Yue; Zeng, Xianqiu; An, Xiaofei; Liu, Zhiping; Wang, Lina; Xu, Jiean; Cao, Yapeng; Fulton, David J; Weintraub, Neal Lee; Bagi, Zsolt; Hoda, MD Nasrul; Wang, Xiaoling; Li, Qinkai; Hong, Mei; Jiang, Xuejun; Boison, Detlev; Weber, Christian; Wu, Chaodong; Huo, Yuqing.

In: EMBO Molecular Medicine, Vol. 9, No. 9, 01.09.2017, p. 1263-1278.

Research output: Contribution to journalArticle

Xu, Y, Wang, Y, Yan, S, Zhou, Y, Yang, Q, Pan, Y, Zeng, X, An, X, Liu, Z, Wang, L, Xu, J, Cao, Y, Fulton, DJ, Weintraub, NL, Bagi, Z, Hoda, MDN, Wang, X, Li, Q, Hong, M, Jiang, X, Boison, D, Weber, C, Wu, C & Huo, Y 2017, 'Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis', EMBO Molecular Medicine, vol. 9, no. 9, pp. 1263-1278. https://doi.org/10.15252/emmm.201607066
Xu, Yiming ; Wang, Yong ; Yan, Siyuan ; Zhou, Yaqi ; Yang, Qiuhua ; Pan, Yue ; Zeng, Xianqiu ; An, Xiaofei ; Liu, Zhiping ; Wang, Lina ; Xu, Jiean ; Cao, Yapeng ; Fulton, David J ; Weintraub, Neal Lee ; Bagi, Zsolt ; Hoda, MD Nasrul ; Wang, Xiaoling ; Li, Qinkai ; Hong, Mei ; Jiang, Xuejun ; Boison, Detlev ; Weber, Christian ; Wu, Chaodong ; Huo, Yuqing. / Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis. In: EMBO Molecular Medicine. 2017 ; Vol. 9, No. 9. pp. 1263-1278.
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AU - Wang, Yong

AU - Yan, Siyuan

AU - Zhou, Yaqi

AU - Yang, Qiuhua

AU - Pan, Yue

AU - Zeng, Xianqiu

AU - An, Xiaofei

AU - Liu, Zhiping

AU - Wang, Lina

AU - Xu, Jiean

AU - Cao, Yapeng

AU - Fulton, David J

AU - Weintraub, Neal Lee

AU - Bagi, Zsolt

AU - Hoda, MD Nasrul

AU - Wang, Xiaoling

AU - Li, Qinkai

AU - Hong, Mei

AU - Jiang, Xuejun

AU - Boison, Detlev

AU - Weber, Christian

AU - Wu, Chaodong

AU - Huo, Yuqing

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N2 - 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.

AB - 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.

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