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Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice.

ABSTRACT: Retinal angiogenesis is a critical process for normal retinal function. However, uncontrolled angiogenesis can lead to pathological neovascularization (NV), which is closely related to most irreversible blindness-causing retinal diseases. Understanding the molecular basis behind pathological NV is important for the treatment of related diseases. Twist-related protein 1 (TWIST1) is a well-known transcription factor and principal inducer of epithelial-mesenchymal transition (EMT) in many human cancers. Our previous study showed that Twist1 expression is elevated in pathological retinal NV. To date, however, the role of TWIST1 in retinal pathological angiogenesis remains to be elucidated. To study the role of TWIST1 in pathological retinal NV and identify specific molecular targets for antagonizing pathological NV, we generated an inducible vascular endothelial cell (EC)-specific Twist1 transgenic mouse model ( Tg-Twist1 ^iEC+ ). Whole-mount retinas from Tg-Twist1 ^iEC+ mice showed retarded vascular progression and increased vascular density in the front end of the growing retinal vasculature, as well as aneurysm-like pathological retinal NV. Furthermore, overexpression of Twist1 in the ECs promoted cell proliferation but disturbed cell polarity, thus leading to uncontrolled retinal angiogenesis. TWIST1 promoted pathological NV by activating the Wnt/β-catenin signaling pathway and inducing the expression of NV formation-related genes, thereby acting as a 'valve' in the regulation of pathological angiogenesis. This study identified the critical role of TWIST1 in retinal pathological NV, thus providing a potential therapeutic target for pathological NV.

SUBMITTER: Zhang L

PROVIDER: S-EPMC8743260 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeThe purpose of this study was to investigate the effects and mechanism of microRNA (miR)-92a-3p in retinal angiogenesis in vitro and in vivo.MethodsThe expression of miR-92a-3p was verified by real-time quantitative polymerase chain reaction (RT-qPCR). Agomir-92a-3p was intravitreally injected into the right eye on postnatal day 3 (P3), P5, and P8 in the mice, with the agomir-NC injected left eye as the control. At P7, P9, and P12, immunofluorescence was performed to examine the retinal superficial vascular plexus, deep vascular plexus, proliferation, and apoptosis in retinal vascular endothelial cells (ECs). Human retinal microvascular endothelial cells (HRMECs) were treated with mimic-NC and mimic-92a-3p, then the tube formation, cell migration, and wound healing assays were used to detect the effect of miR-92a-3p on retinal angiogenesis in vitro. Agomir-92a-3p was also intravitreally injected into the right eye of oxygen-induced retinopathy (OIR) mice at P12, with the agomir-NC injected left eye as the control, the neovascularization was observed by retinal flatmount staining with isolectin B4 at P17. Bioinformatics and high-throughput sequencing were performed to identify potential target genes of miR-92a-3p. RT-qPCR and Western blot were carried out to detect the expression of SGK3, p-GSK3β, GSK3β, Bcl-xL, and cleaved caspase-3 in the HRMECs and mouse retinas.ResultsThe overexpression of miR-92a-3p inhibited the development of retinal superficial vascular plexus and deep vascular plexus, decreased the expression of Ki67, and increased the expression of cleaved caspase-3 in isolectin B4-labeled retinal vascular ECs. In vitro, the overexpression of miR-92a-3p markedly suppressed the tube formation, cell migration, and wound healing of cultured ECs. Overexpression of miR-92a-3p inhibited both in vivo and in vitro physiological angiogenesis by downregulating the expression of SGK3, p-GSK3β/GSK3β, and Bcl-xL. In addition, agomir-92a-3p inhibited the pathological retinal neovascularization of OIR mice, by targeting SGK3, p-GSK3β/GSK3β, and Bcl-xL.ConclusionsThe miR-92a-3p could affect retinal angiogenesis by targeting SGK3 pathway, suggesting that miR-92a-3p may be a potential anti-angiogenic factor for retinal vascular disease.

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Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice.

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