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

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 (EP₄R). The aim of this study was to investigate the role of PGE₂/EP₄R 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 EP₄R agonist) or AH23848 (an EP₄R 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/EP₄R signaling network is thus a potential therapeutic target for pathological intraocular angiogenesis.

Keywords: EGF receptor; EP(4)R; Endothelial cell; PGE(2); Retinal angiogenesis.