Silencing of S100A4, a metastasis-associated protein, inhibits retinal neovascularization via the downregulation of BDNF in oxygen-induced ischaemic retinopathy

Abstract

Background To investigate the underlying mechanism of S100A4 function and whether it has a role in retinal neovascularization (RNV) in a mouse model of oxygen-induced retinopathy (OIR). Methods Retinas from a mouse model of OIR were treated with and without an intravitreous injection of adenoviral-S100A4-RNAi or adenoviral green fluorescence protein (GFP) at postnatal day 12 (P12). At P17, the efficacy of adenoviral gene transfer was assessed using fluorescence microscopy and western blot analysis. RNV was evaluated by wholemount immunofluorescence staining of the mouse retina and by counting the number of pre-retinal neovascular cells. Protein and mRNA expression levels of S100A4, brainderived growth factor (BDNF), and vascular endothelial growth factor (VEGF) were measured using western blot analysis and real-time PCR. Results Retinal S100A4 levels were positively correlated with the progression of RNV. In the OIR-S100A4-RNAi group, both protein and mRNA expression levels of S100A4 in the retina significantly decreased at P17 compared with those in the OIR group. Ad-S100A4-RNAi transfer was clearly demonstrated by GFP fluorescence in many layers of the retina 5 days after the Ad-S100A4-RNAi transfer. Whole-mount immunofluorescence staining of the retina and quantification of the pre-retinal neovascular cells demonstrated that RNV was significantly inhibited. Meanwhile, the levels of the transcription and translation of BDNF,

S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/mTOR Signaling Pathway

“… 11 In addition, retinal neovascularization can be ameliorated by inhibition of S100A4 in an oxygen-induced retinopathy mouse model. 35 , 36 On the basis of those findings, our study put forward a way for corneal repair by targeting S100A4.…”

Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies

“…It regulates the expression of S100A4 in fibroblast-regulated intestinal and pulmonary tissue fibrosis [ 51 , 52 ]. Research indicates that S100A4 confers idiopathic pulmonary fibrosis lungs harboring fibrogenic mesenchymal progenitor cells with fibrogenicity [ 53 ]. Hypertrophic scars in tissues, followed by fibrosis induced by TNF-α, lead to an increase in MMP, S100A4, and vimentin expression, which can be antagonized by bone morphogenetic protein 2/4 [ 54 ].…”

“…Research has shown that S100A4 is a pro-angiogenic factor that participates in angiogenesis, endothelial cell migration and invasion via its interaction with annexin 2, formation of plasmin, and stimulation of MMP production [ 78 , 79 ]. S100A4-mediated angiogenesis also functions synergistically with the vascular endothelial growth factor, which is an important angiogenic factor that promotes neo-vascularization and vascular leakage through an upstream regulator, the brain-derived growth factor [ 53 , 78 ].…”

“…Recently, RAGE located on the surface of human endothelial cells was reported to be utilized by S100A4 to enhance endothelial cell migration and neovascularization. This helps the cells associated with other angiogenic factors and achieve angiogenesis-related responses [ 53 , 80 ].…”

“…Additionally, S100A4 can be a target for the treatment of periodontitis, which inhibits osteogenic differentiation and enhances matrix degradation [ 35 ]. The study showing that silencing of the mouse S100A4 gene ameliorates retinal neovascularization in a mouse model indicates that knockdown of S100A4 may be an effective treatment for ocular neovascularization diseases [ 53 ]. Furthermore, therapy targeting S100A4 can suppress the progression of rheumatoid arthritis and persistent high S100A4 expression will predict poor treatment outcome of rheumatoid arthritis [ 101 ].…”