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Prostaglandin E2 Promotes Pathological Retinal Neovascularization via EP4R-EGFR-Gab1 Signalling Pathway

43 Pages Posted: 14 Mar 2019

See all articles by Zhonghong Zhang

Zhonghong Zhang

Nanjing Medical University - Department of Ophthalmology

Xubin Pan

Nanjing Medical University - Department of Ophthalmology

Pengfei Zhan

Nanjing Medical University - Department of Ophthalmology

Yanqiu Liu

Nanjing Medical University - Department of Ophthalmology

Man Wang

Nanjing Medical University - Department of Ophthalmology

Yishun Shu

Nanjing Medical University - Department of Ophthalmology

Yangningzhi Wang

Nanjing Medical University - Department of Ophthalmology

Wenjuan Wang

Nanjing Medical University - Center of Clinical Research

Tingting Wei

Nanjing Medical University - Center of Clinical Research

Lingpeng Zhu

Nanjing Medical University - Center of Clinical Research

Jian Zou

Nanjing Medical University - Center for Clinical Research; Nanjing Medical University - Wuxi Institute of Translational Medicine

Xiaowei Nie

Nanjing Medical University - Center of Clinical Research

Jing Leng

Nanjing Medical University

Yong Yao

Nanjing Medical University - Department of Ophthalmology

Tianhua Xie

Nanjing Medical University - Department of Ophthalmology

Xiaolu Wang

Nanjing Medical University - Center of Clinical Research

More...

Abstract

Background: Proliferative retinopathies, such as retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR) are major causes of visual impairment and blindness in industrialized countries. The rat oxygen-induced retinopathy (OIR) model is a well-established animal model for forms of pathological angiogenesis. PGE2, the major product of cyclooxygenases, is implicated in cellular proliferation, angiogenesis and migration via prostanoid receptor EP4. The aim of this study was to investigate the role of PGE2 and its EP4 receptor (EP4R) in the promotion of retinal neovascularization.  

Methods: In an OIR-induced rat model and a streptozotocin (STZ)-induced PDR model of pathological retinal angiogenesis, rats received an intravitreal injection of PGE2, Cay10598 (an EP4R agonist) or AH23848 (an EP4R antagonist). Optical coherence tomography, retinal histology and biochemical markers were assessed.  

Findings: Intravitreal injection of PGE2 and Cay10598 significantly accelerated pathological retinal angiogenesis in OIR-induced rat retina and endothelial tip-cell formation in newborn rat retina. Treatment with PGE2 or Cay10598 also accelerated retinal NV in STZ-induced diabetic rats, which was ameliorated in rats pretreated with AH23848. In addition, pretreatment of human retinal microvascular endothelial cells (hRMECs) with AH23848 attenuated PGE2- or Cay10598- induced proliferation and migration by repressing the EGFR/Gab1/Akt signalling network.  

Interpretation: These results indicate that PGE2/EP4R mediated hRMECs proliferation by promoting the activation of the EGFR/Gab1/Akt signalling pathway and that this network is thus a potential therapeutic target for pathological intraocular angiogenesis.  

Funding: This work was supported by grants from the National Natural Science Foundation of China (no. 81770941 and 81800845), Jiangsu Key Medical Disciplines (ZDXKC2016008), Technology Development Fund (CSE12N1701), Wuxi Eminent Medical Talents (JCRC005 and QNRC077) and Young project of Wuxi health and Family Planning Commission (Q201707).

Declaration of Interest: The authors declare no conflicts of interest.

Ethical Approval: A written informed consent was obtained from all the participants before the study, and the study was approved by the hospital ethics committee. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.

Keywords: PGE2, EP4R, Oxygen-induced retinopathy (OIR), Neovascularisation (NV), Endothelial cell

Suggested Citation

Zhang, Zhonghong and Pan, Xubin and Zhan, Pengfei and Liu, Yanqiu and Wang, Man and Shu, Yishun and Wang, Yangningzhi and Wang, Wenjuan and Wei, Tingting and Zhu, Lingpeng and Zou, Jian and Nie, Xiaowei and Leng, Jing and Yao, Yong and Xie, Tianhua and Wang, Xiaolu, Prostaglandin E2 Promotes Pathological Retinal Neovascularization via EP4R-EGFR-Gab1 Signalling Pathway (March 13, 2019). Available at SSRN: https://ssrn.com/abstract=3351985

Zhonghong Zhang

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Xubin Pan

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Pengfei Zhan

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Yanqiu Liu

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Man Wang

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Yishun Shu

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Yangningzhi Wang

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Wenjuan Wang

Nanjing Medical University - Center of Clinical Research

Jiangsu
China

Tingting Wei

Nanjing Medical University - Center of Clinical Research

Jiangsu
China

Lingpeng Zhu

Nanjing Medical University - Center of Clinical Research

Jiangsu
China

Jian Zou

Nanjing Medical University - Center for Clinical Research ( email )

299 Qingyang Road
Wuxi, Jiangsu 214023
China

Nanjing Medical University - Wuxi Institute of Translational Medicine ( email )

Wuxi, Jiangsu 214023
China

Xiaowei Nie

Nanjing Medical University - Center of Clinical Research

Jiangsu
China

Jing Leng

Nanjing Medical University

300 Guangzhou Road
Nanjing, Jiangsu 210029
China

Yong Yao (Contact Author)

Nanjing Medical University - Department of Ophthalmology ( email )

Jiangsu
China

Tianhua Xie

Nanjing Medical University - Department of Ophthalmology ( email )

Jiangsu
China

Xiaolu Wang

Nanjing Medical University - Center of Clinical Research ( email )

Jiangsu
China

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