PGF _2α facilitates pathological retinal angiogenesis by modulating endothelial FOS ‐driven ELR ⁺ CXC chemokine expression

Abstract

The pathological retinal angiogenesis often causes blindness. Current anti‐angiogenic therapy for proliferative retinopathy targets the vascular endothelial growth factor (VEGF), but many patients do not radically benefit from this therapy. Herein, we report that circulating prostaglandin (PG) F2α metabolites were increased in type 2 diabetic patients with proliferative retinopathy, and the PGF2α receptor (Ptgfr) was upregulated in retinal endothelial cells (ECs) from a mouse model of oxygen‐induced retinopathy (OIR). Further, disruption of the PTGFR receptor in ECs attenuated OIR in mice. PGF2α promoted the proliferation and tube formation of human retinal microvascular endothelial cells (HRMECs) via the release of ELR+ CXC chemokines, such as CXCL8 and CXCL2. Mechanistically, the PGF2α/PTGFR axis potentiated ELR+ CXC chemokine expression in HRMECs through the Gq/CAMK2G/p38/ELK‐1/FOS pathway. Upregulated FOS‐mediated ELR+ CXC chemokine expression was observed in retinal ECs from PDR patients. Moreover, treatment with PTGFR inhibitor lessened the development of OIR in mice in a CXCR2‐dependent manner. Therefore, inhibition of PTGFR may represent a new avenue for the treatment of retinal neovascularization, particularly in PDR.

Prostaglandin F2α Affects the Cycle of Clock Gene Expression and Mouse Behavior

“…Although Ptgfr is expressed in organs throughout the body, it is highly expressed in the uterus and retina [17,22]. Circadian rhythms in prostaglandin E 2 secretion in serum and prostaglandin D synthase expression in the brain have also been observed [16,23,24].…”

“…Although Ptgfr is expressed in organs throughout the body, it is highly expressed the uterus and retina [17,22]. Circadian rhythms in prostaglandin E2 secretion in seru and prostaglandin D synthase expression in the brain have also been observed [16,23,2 To clarify the activation rhythm of the Ptgfr cascade in the retina, we measured the expre sion rhythm of Ptgfr in the retinas of wild-type mice using an RT-qPCR system.…”

“…Prostaglandin F 2α (PGF 2α ) is a subtype of prostaglandin that acts on blood vessels around the glomus body and retinal arteries [17]. The prostaglandin F receptor (PTGFR) is localized in the eye and uterus, where its ligand binding activates PKC and AMPK [18].…”

Inflammatory cytokines as mediators of retinal endothelial barrier dysfunction in non‐infectious uveitis

“…CXCR1 interacts only with IL‐8 and CXCL‐6, whereas CXCR2 binds more broadly to CXC chemokines 173 . Multiple cell types express CXCR1 and CXCR2, including T cells, neutrophils, fibroblasts, epithelial cells and vascular endothelial cells, 174 while human retinal endothelial cells express CXCR2 but not CXCR1 175 . Following binding of IL‐8 to its receptor, several signalling pathways are activated, including pathways mediated by PI3Kγ, phospholipase C, and tyrosine‐protein kinase HCK, small GTPases Ras/Rac/Rho/cdc42/Rap1, protein kinase C (PKC) and AKT.…”

“… 173 Multiple cell types express CXCR1 and CXCR2, including T cells, neutrophils, fibroblasts, epithelial cells and vascular endothelial cells, 174 while human retinal endothelial cells express CXCR2 but not CXCR1. 175 Following binding of IL‐8 to its receptor, several signalling pathways are activated, including pathways mediated by PI3Kγ, phospholipase C, and tyrosine‐protein kinase HCK, small GTPases Ras/Rac/Rho/cdc42/Rap1, protein kinase C (PKC) and AKT. Interleukin‐8 has been shown to promote cell adhesion, cytoskeletal changes, membrane protrusion, cell migration, exocytosis of lysosomal enzymes and endothelial permeability.…”