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Published on: December 9, 2022
PGF2α facilitates pathological retinal angiogenesis by modulating endothelial FOS-driven ELR+ CXC chemokine
Yan Zhao1,2, Yi Lei3, Huying Ning1
1Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
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.
Insights
Prostaglandin F2α (PGF2α) signaling through its receptor (PTGFR) drives pathological retinal neovascularization in diabetic retinopathy. Inhibiting PTGFR offers a potential new treatment for this blinding condition.
Area of Science:
- Ophthalmology
- Endocrinology
- Molecular Biology
Background:
- Pathological retinal angiogenesis, a hallmark of proliferative retinopathy, is a leading cause of blindness.
- Current anti-vascular endothelial growth factor (VEGF) therapies are not effective for all patients with proliferative retinopathy.
Purpose of the Study:
- To investigate the role of prostaglandin F2α (PGF2α) and its receptor (PTGFR) in pathological retinal neovascularization.
- To explore the therapeutic potential of targeting the PGF2α/PTGFR axis in proliferative diabetic retinopathy (PDR).
Main Methods:
- Measured circulating PGF2α metabolites in type 2 diabetic patients with proliferative retinopathy.
- Assessed PGF2α receptor (Ptgfr) expression in a mouse model of oxygen-induced retinopathy (OIR).
- Investigated the effects of PGF2α on human retinal microvascular endothelial cells (HRMECs) and the underlying molecular pathways (Gq/CAMK2G/p38/ELK-1/FOS).
Main Results:
- Elevated PGF2α metabolites were found in patients with proliferative retinopathy.
- Ptgfr was upregulated in retinal endothelial cells (ECs) in OIR mice, and its disruption attenuated OIR.
- PGF2α promoted HRMEC proliferation and tube formation via ELR+ CXC chemokines (e.g., CXCL8, CXCL2) through the PGF2α/PTGFR/FOS pathway.
- PTGFR inhibition reduced OIR development in mice.
Conclusions:
- The PGF2α/PTGFR axis promotes retinal neovascularization by upregulating ELR+ CXC chemokines.
- Targeting PTGFR represents a promising therapeutic strategy for treating retinal neovascularization, especially in PDR.
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