Prostaglandin E2 promotes pathological retinal neovascularisation via EP4R-EGFR-Gab1-AKT signaling pathway

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 E 2 (PGE 2 ) is implicated in cellular proliferation and migration via E-prostanoid receptor (EP 4 R). The aim of this study was to investigate the role of PGE 2 /EP 4 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 PGE 2 , cay10598 (an EP 4 R agonist) or AH23848 (an EP 4 R antagonist). Optical coherence tomography, retinal histology and biochemical markers were assessed. Treatment with PGE 2 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 PGE 2 -treated diabetic rats vs non-treated diabetic rats and significantly downregulated in AH23848-treated diabetic rats. PGE 2 or cay10598 treatment also significantly accelerated endothelial tip-cell formation in new-born rat retina. In addition, AH23848 treatment attenuated PGE 2 -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). PGE 2 /EP 4 R signaling network is thus a potential therapeutic target for pathological intraocular angiogenesis. • Prostaglandin E 2 is a crucial growth-factor inducer and a potent proangiogenic mediator. • PGE 2 /EP 4 R cascade actually mediates retinal angiogenesis via transactivation of EGFR. • The PGE 2 /EP 4 R pathway could be a therapeutic target for pathological angiogenesis prevention and treatment in the retina.