Prostaglandin E 2 promotes pathological retinal neovascularisation via EP 4 R-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.
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