Prostaglandin E2 promotes pathological retinal neovascularisation via EP4R-EGFR-Gab1-AKT signaling pathway. (April 2021)

• Record Type: Journal Article
• Authors: Xie, Tianhua; Zhang, Zhonghong; Cui, Yuqing; Shu, Yishun; Liu, Yanqiu; Zou, Jian; Wang, Man; Wang, Yangningzhi; Yang, Qian; Pan, Xubin; Cai, Jiping; Sun, Xiaodong; Yao, Yong; Wang, Xiaolu
• Is Part Of: Experimental eye research. Volume 205(2021)
• Publication Date: 2021-04
• Subjects: PGE2 -- EP4R -- EGF receptor -- Retinal angiogenesis -- Endothelial cell; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2021.108507
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Proliferative retinopathies, such as proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) are major causes of visual impairment and blindness in industrialized countries. Prostaglandin E2 (PGE2 ) is implicated in cellular proliferation and migration via E-prostanoid receptor (EP4 R). The aim of this study was to investigate the role of PGE2 /EP4 R signaling in the promotion of retinal neovascularisation. In a streptozotocin (STZ)-induced diabetic model and an oxygen-induced retinopathy (OIR) model, rats received an intravitreal injection of PGE2, cay10598 (an EP4 R agonist) or AH23848 (an EP4 R antagonist). Optical coherence tomography, retinal histology and biochemical markers were assessed. Treatment with PGE2 or cay10598 accelerated pathological retinal angiogenesis in STZ and OIR-induced rat retina, which was ameliorated in rats pretreated with AH23848. Serum VEGF-A was upregulated in the PGE2 -treated diabetic rats vs non-treated diabetic rats and significantly downregulated in AH23848-treated diabetic rats. PGE2 or cay10598 treatment also significantly accelerated endothelial tip-cell formation in new-born rat retina. In addition, AH23848 treatment attenuated PGE2 -or cay10598-induced proliferation and migration by repressing the EGF receptor (EGFR)/Growth factor receptor bound protein 2-associated binder protein 1 (Gab1)/Akt/NF-κB/VEGF-A signaling network in human retinal microvascular endothelial cells (hRMECs). PGE2 /EP4 R signaling network is thus a potential therapeutic target for pathological intraocular angiogenesis. Graphical abstract: Image 1 Highlights: Prostaglandin E2 is a crucial growth-factor inducer and a potent proangiogenic mediator. PGE2 /EP4 R cascade actually mediates retinal angiogenesis via transactivation of EGFR. The PGE2 /EP4 R pathway could be a therapeutic target for pathological angiogenesis prevention and treatment in the retina.