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The anti-angiogenic role of discoidin domain receptor 2 (DDR2) in laser-induced choroidal neovascularization

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Abstract

Choroidal neovascularization (CNV), an aberrant growth of blood vessels in the choroid layer of the eye, is a major cause of vision loss. In view of our recent finding that discoidin domain receptor 2 (DDR2), a collagen-binding receptor tyrosine kinase, is involved in control of vascular endothelial activity and tumor angiogenesis, the present study aims to investigate whether and how DDR2 affects the pathogenesis of CNV. We initially found that a spontaneous DDR2 mutant mouse colony (slie) exhibited enhanced amplitude of laser-induced CNV. The inhibitory role of DDR2 in CNV development was further confirmed by experiments through intravitreous injection of DDR2 small interference RNA (siRNA) or DDR2-expressing adenovirus. Quantitative real-time polymerase chain reaction (qPCR) and immunoblot analysis showed that DDR2 regulates the expression of several major pro-angiogenic factors in the laser-injured choroid as well as in retinal pigment epithelium (RPE) cells. In addition, it was demonstrated that the CNV-induced increases in the phosphorylation levels of Akt and mTOR were affected by the upregulation or downregulation of DDR2. Thus, the data from this study for the first time revealed that DDR2 negatively regulates the development of experimental CNV in vivo, which may provide a novel target for preventing human pathological ocular neovascularization.

Key messages

  • DDR2 does not affect retinal development.

  • DDR2 inhibits laser-induced CNV.

  • DDR2 regulates angiogenic factor expression in CNV lesion as well as in RPE cells.

  • DDR2 is involved in modulation of CNV-induced activation of PI3K pathway.

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Acknowledgments

We greatly thank Dr. Wei Zhang (The Fourth Military Medical University, Xi’an, China) for providing us the DDR2-expressing adenovirus stock.

Funding

This work was supported by the National Natural Science Foundation of China (81070748, 81000392) and grants from the Chinese National Key Basic Research and Development Program (2011CB510200 and 2010CB529705).

Conflict of interest

The authors declare no competing or financial interests.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Xijing Hospital, The Fourth Military Medical University, 169 Changle Western Road, Xi’an, 710032, China

    Tong Zhu, Jie Zhu, Yuan Chang, Rong Li & Yusheng Wang

  2. State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle Western Road, Xi’an, 710032, China

    Xin Bu, Hu Zhao, Libo Yao & Jin Su

  3. Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, China

    Shuya Zhang

  4. Affiliated hospital of Xi’an Medical University, Xi’an, 710077, China

    Rong Li

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  1. Tong Zhu
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  2. Jie Zhu
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  3. Xin Bu
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  4. Hu Zhao
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  9. Yusheng Wang
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  10. Jin Su
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Correspondence to Yusheng Wang or Jin Su.

Additional information

Tong Zhu and Jie Zhu and Xin Bu equally contribute to this paper.

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Zhu, T., Zhu, J., Bu, X. et al. The anti-angiogenic role of discoidin domain receptor 2 (DDR2) in laser-induced choroidal neovascularization. J Mol Med 93, 187–198 (2015). https://doi.org/10.1007/s00109-014-1213-7

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  • DOI: https://doi.org/10.1007/s00109-014-1213-7

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