Adenosine A1 receptors selectively modulate oxygen- induced retinopathy at the hyperoxic and hypoxic phases by distinct cellular mechanisms

Shuya Zhang, Haiyan Li, Bo Li, Dingjuan Zhong, Xuejiao Gu, Lingyun Tang, Yanyan Wang, Cun Wang, Rong Zhou, Yan Li, Yan He, Mozi Chen, Yuqing Huo, Xiao Ling Liu, Jiang Fan Chen

Research output: Contribution to journalArticle

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Abstract

Purpose: We critically evaluated the role of the adenosine A1receptor (A1R) in normal development of retinal vasculature and pathogenesis of retinopathy of prematurity (ROP) by using the A1R knockout (KO) mice and oxygen-induced retinopathy (OIR) model. Methods: Mice deficient in A1Rs and their wild-type (WT) littermates were examined during normal postnatal development or after being subjected to 75% oxygen from postnatal day (P) 7 to P12 and to room air from P12 to P17 (OIR model of ROP). Retinal vascularization was examined by whole-mount fluorescence and cross-sectional hematoxylin-eosin staining. Cellular proliferation, astrocyte and microglial activation, and tip cell function were determined by isolectin staining and immunohistochemistry. Apoptosis was determined by TUNEL assay. Results: Genetic deletion of the A1R did not affect normal retinal vascularization during postnatal development with indistinguishable three-layer vascularization patterns in retina between WT and A1R KO mice. In the OIR model, genetic deletion of the A1R resulted in stage-specific effects: reduced hyperoxia-induced retinal vaso-obliteration at P12, but reduced avascular area and attenuated hypoxia-induced intraretinal revascularization without affecting intravitreal neovascularization at P17 and reduced avascular areas in retina at P21. These distinct effects of A1Rs on OIR were associated with A1R control of apoptosis mainly in inner and outer nuclear layers at the vaso-obliterative phase (P12) and the growth of endothelium tip cells at the vasoproliferative phase (P17), without modification of cellular proliferation, astrocytic activation, and tissue inflammation. Conclusions: Adenosine A1 receptor activity is not required for normal postnatal development of retinal vasculature but selectively controls hyperoxia-induced vaso-obliteration and hypoxia-driven revascularization by distinct cellular mechanisms.

Original languageEnglish (US)
Pages (from-to)8108-8119
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number13
DOIs
StatePublished - Dec 2015

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Adenosine A1 Receptors
Oxygen
Retinopathy of Prematurity
Hyperoxia
Knockout Mice
Retina
Cell Proliferation
Apoptosis
Staining and Labeling
In Situ Nick-End Labeling
Hematoxylin
Eosine Yellowish-(YS)
Lectins
Astrocytes
Adenosine
Endothelium
Fluorescence
Immunohistochemistry
Air
Inflammation

Keywords

  • Adenosine A receptor
  • Endothelial tip cells
  • Neovascularization
  • Oxygen-induced retinopathy
  • Proliferative retinopathy
  • Retinal revascularization
  • Vaso-obliteration

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Adenosine A1 receptors selectively modulate oxygen- induced retinopathy at the hyperoxic and hypoxic phases by distinct cellular mechanisms. / Zhang, Shuya; Li, Haiyan; Li, Bo; Zhong, Dingjuan; Gu, Xuejiao; Tang, Lingyun; Wang, Yanyan; Wang, Cun; Zhou, Rong; Li, Yan; He, Yan; Chen, Mozi; Huo, Yuqing; Liu, Xiao Ling; Chen, Jiang Fan.

In: Investigative Ophthalmology and Visual Science, Vol. 56, No. 13, 12.2015, p. 8108-8119.

Research output: Contribution to journalArticle

Zhang, S, Li, H, Li, B, Zhong, D, Gu, X, Tang, L, Wang, Y, Wang, C, Zhou, R, Li, Y, He, Y, Chen, M, Huo, Y, Liu, XL & Chen, JF 2015, 'Adenosine A1 receptors selectively modulate oxygen- induced retinopathy at the hyperoxic and hypoxic phases by distinct cellular mechanisms', Investigative Ophthalmology and Visual Science, vol. 56, no. 13, pp. 8108-8119. https://doi.org/10.1167/iovs.15-17202
Zhang, Shuya ; Li, Haiyan ; Li, Bo ; Zhong, Dingjuan ; Gu, Xuejiao ; Tang, Lingyun ; Wang, Yanyan ; Wang, Cun ; Zhou, Rong ; Li, Yan ; He, Yan ; Chen, Mozi ; Huo, Yuqing ; Liu, Xiao Ling ; Chen, Jiang Fan. / Adenosine A1 receptors selectively modulate oxygen- induced retinopathy at the hyperoxic and hypoxic phases by distinct cellular mechanisms. In: Investigative Ophthalmology and Visual Science. 2015 ; Vol. 56, No. 13. pp. 8108-8119.
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AU - Li, Haiyan

AU - Li, Bo

AU - Zhong, Dingjuan

AU - Gu, Xuejiao

AU - Tang, Lingyun

AU - Wang, Yanyan

AU - Wang, Cun

AU - Zhou, Rong

AU - Li, Yan

AU - He, Yan

AU - Chen, Mozi

AU - Huo, Yuqing

AU - Liu, Xiao Ling

AU - Chen, Jiang Fan

PY - 2015/12

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N2 - Purpose: We critically evaluated the role of the adenosine A1receptor (A1R) in normal development of retinal vasculature and pathogenesis of retinopathy of prematurity (ROP) by using the A1R knockout (KO) mice and oxygen-induced retinopathy (OIR) model. Methods: Mice deficient in A1Rs and their wild-type (WT) littermates were examined during normal postnatal development or after being subjected to 75% oxygen from postnatal day (P) 7 to P12 and to room air from P12 to P17 (OIR model of ROP). Retinal vascularization was examined by whole-mount fluorescence and cross-sectional hematoxylin-eosin staining. Cellular proliferation, astrocyte and microglial activation, and tip cell function were determined by isolectin staining and immunohistochemistry. Apoptosis was determined by TUNEL assay. Results: Genetic deletion of the A1R did not affect normal retinal vascularization during postnatal development with indistinguishable three-layer vascularization patterns in retina between WT and A1R KO mice. In the OIR model, genetic deletion of the A1R resulted in stage-specific effects: reduced hyperoxia-induced retinal vaso-obliteration at P12, but reduced avascular area and attenuated hypoxia-induced intraretinal revascularization without affecting intravitreal neovascularization at P17 and reduced avascular areas in retina at P21. These distinct effects of A1Rs on OIR were associated with A1R control of apoptosis mainly in inner and outer nuclear layers at the vaso-obliterative phase (P12) and the growth of endothelium tip cells at the vasoproliferative phase (P17), without modification of cellular proliferation, astrocytic activation, and tissue inflammation. Conclusions: Adenosine A1 receptor activity is not required for normal postnatal development of retinal vasculature but selectively controls hyperoxia-induced vaso-obliteration and hypoxia-driven revascularization by distinct cellular mechanisms.

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KW - Endothelial tip cells

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KW - Oxygen-induced retinopathy

KW - Proliferative retinopathy

KW - Retinal revascularization

KW - Vaso-obliteration

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