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

Xie, Ting; Zhang, Zhonghong; Cui, Yuqing; Shu, Yishun; Li, Yanqiu; Zou, Jian; Wang, Man; Wang, Yangningzhi; Yang, Qian; Cai, Jiping; Sun, Xiaodong; Yao, Yong; Wang, Xiaolu

doi:10.1016/j.exer.2021.108507

Cited by 13 publications

(8 citation statements)

References 52 publications

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“…Other reviews describe separate pathways where cytokines, for example, directly mediate leakage independent of VEGF ( Figure 1 ) [ 22 , 23 , 24 , 25 ]. There is literature supporting both views—for example, the cytokine prostaglandin E2 can directly cause vascular leakage and proliferation but can also upregulate VEGF [ 26 , 27 , 28 , 29 ]. Both pathways likely play some role in the development of leakage.…”

Section: Introductionmentioning

confidence: 99%

Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options

Wallsh

Gallemore

2021

Cells

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Anti-vascular endothelial growth factor (anti-VEGF) therapy currently plays a central role in the treatment of numerous retinal diseases, most notably exudative age-related macular degeneration (eAMD), diabetic retinopathy and retinal vein occlusions. While offering significant functional and anatomic benefits in most patients, there exists a subset of 15–40% of eyes that fail to respond or only partially respond. For these cases, various treatment options have been explored with a range of outcomes. These options include steroid injections, laser treatment (both thermal therapy for retinal vascular diseases and photodynamic therapy for eAMD), abbreviated anti-VEGF treatment intervals, switching anti-VEGF agents and topical medications. In this article, we review the effectiveness of these treatment options along with a discussion of the current research into future directions for anti-VEGF-resistant eyes.

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Section: Introductionmentioning

confidence: 99%

Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options

Wallsh

Gallemore

2021

Cells

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“…PGE 2 is an important factor for cell growth and regulation, which is a metabolite of the arachidonic acid COX, and their role has been reported in many disorders, including tumour metastasis, rheumatoid arthritis, asthma and inflammatory diseases [ 28 – 30 ]. Increasing evidence has proved that PGE 2 is involved in the retinopathy of prematurity (ROP), diabetic retinopathy, pterygium and other ocular neovascular diseases [ 18 ]. We found that the PGE 2 expression increased in the eyes after induction of the laser injury.…”

Section: Discussionmentioning

confidence: 99%

“…The analysis of the NF-κB binding activity in the nuclear proteins was performed as described in our previous study [ 18 ]. The NF-κB binding activity was examined using a Light Shift Chemiluminescent EMSA kit (Thermo Fisher Scientific #20,148) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

PGE2 promotes macrophage recruitment and neovascularization in murine wet-type AMD models

et al. 2022

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Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is a leading cause of blindness worldwide. Activated macrophages recruited to the injured eyes greatly contribute to the pathogenesis of choroidal neovascularization (CNV) in exudative AMD (wet AMD). This study describes the effects of cyclooxygenase-2 (COX2)/prostaglandin E2 (PGE2) signalling on the macrophage activation and CNV formation of wet AMD. In a mouse model of laser-induced wet AMD, the mice received an intravitreal injection of celecoxib (a selective COX2 inhibitor). Optical coherence tomography (OCT), fundus fluorescein angiography (FFA), choroidal histology of the CNV lesions, and biochemical markers were assessed. The level of PGE2 expression was high in the laser-induced CNV lesions. Macrophage recruitment and CNV development were significantly less after celecoxib treatment. E-prostanoid1 receptor (EP1R)/protein kinase C (PKC) signalling was involved in M2 macrophage activation and interleukin-10 (IL-10) production of bone marrow-derived macrophages (BMDMs) in vitro. In addition, IL-10 was found to induce the proliferation and migration of human choroidal microvascular endothelial cells (HCECs). Thus, the PGE2/EP1R signalling network serves as a potential therapeutic target for CNV of the wet-type AMD. Graphical Abstract

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“…The previous studies have indicated that EGFR inhibitors played the important role in attenuating inflammatory infiltration and angiogenesis in mice with diabetic retinopathy [ 36 ]. Another in vivo study indicated that it can prevent pathological retinal neovascularization via inhibiting EP (4)R-EGFR-Gab1-AKT signaling pathway [ 37 ]. Studies and experiments have certified that regulating the EGFR pathway also could inhibit the proliferation, migration, and invasion of endothelial cells and retinal pericytes of diabetic retinopathy rats [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Investigating the Mechanisms of Pollen Typhae in the Treatment of Diabetic Retinopathy Based on Network Pharmacology and Molecular Docking

Zhou

Jin

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. To explore the main bioactive compounds and investigate the underlying mechanism of Pollen Typhae (PT) against diabetic retinopathy (DR) by network pharmacology and molecular docking analysis. Methods. Bioactive ingredients and the target proteins of PT were obtained from TCMSP, and the related target genes were acquired from the SwissTargetPrediction database. The target genes of DR were obtained from GeneCards, TTD database, DisGeNET database, and DrugBank. The compound-target interaction network was established based on Cytoscape 3.7.2. The protein-protein interaction (PPI) network was constructed via STRING database and Cytoscape 3.7.2. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were visualized through DAVID database and Bioinformatics. Ingredient-gene-pathway network analysis was conducted to further screen the ingredients, target proteins, and pathways closely related to the biological mechanism on PT for DR, and molecular docking analysis was performed by SYBYL-X 2.1.1 software. Finally, the mechanism and underlying targets of PT in the treatment of DR were predicted. Results. A total of 8 compounds and 171 intersection targets were obtained based on the online network database. 7 main compounds were screened from compound-target network, and 53 targets including the top six key targets (PTGS2, AKT1, VEGFA, MAPK3, TNF, and EGFR) were further acquired from PPI analysis. The 53 key targets covered 80 signaling pathways, among which PI3K-Akt signaling pathway, focal adhesion, Rap1 signaling pathway, VEGF signaling pathway, and HIF-1 signaling pathway were closely connected with the biological mechanism involved in the alleviation of DR by PT. Ingredient-gene-pathway network shows that AKTI, EGFR, and VEGFA were core genes, kaempferol and isorhamnetin were pivotal ingredients, and VEGF signaling pathway and Rap1 signaling pathway were closely involved in anti-DR. The docking results indicated that five main compounds (arachidonic acid, isorhamnetin, quercetin, kaempferol, and (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one) had good binding activity with EGFR and AKT1 targets. Conclusion. The active ingredients in PT may regulate the levels of inflammatory factors, suppress the oxidative stress, and inhibit the proliferation, migration, and invasion of retinal pericytes by acting on PTGS2, AKT1, VEGFA, MAPK3, TNF, and EGFR targets through VEGF signaling pathway, PI3K-Akt signaling pathway, Rap1 signaling pathway, and HIF-1 signaling pathway to play a therapeutic role in diabetic retinopathy.

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

Cited by 13 publications

References 52 publications

Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options

Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options

PGE2 promotes macrophage recruitment and neovascularization in murine wet-type AMD models

Investigating the Mechanisms of Pollen Typhae in the Treatment of Diabetic Retinopathy Based on Network Pharmacology and Molecular Docking

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