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

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.