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An Alkali-burn Injury Model of Corneal Neovascularization in the Mouse
Published on: April 7, 2014
The CXCR4/miR-1910-5p/MMRN2 Axis Is Involved in Corneal Neovascularization by Affecting Vascular Permeability
Xiao Wang1,2, Zedu Cui1,2, Xi Chen1,2
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No. 7 Jinsui Road, Tianhe District, Guangzhou, China.
Purpose:
Chemokine receptor 4 (CXCR4) plays an essential role in the early stage of corneal neovascularization (CNV), but the underlying key molecular mechanism has yet to be addressed. This study aimed to explore the new molecular mechanism of CXCR4 in CNV and the related pathological events.
Methods:
CXCR4 was assayed by immunofluorescence or Western blotting. The function of the supernatant from hypoxia-treated human corneal epithelial cells (HCE-T) cells was examined by culturing with human umbilical vein endothelial cells. MicroRNA sequencing was used to detect the downstream microRNAs upon CXCR4 knockdown and analyzed by preliminary bioinformatics. The proangiogenic functions and downstream target genes of microRNA were investigated by gene interference and luciferase assay. An alkali-burned murine model was introduced to examine the function and mechanism of miR-1910-5p in vivo.
Results:
High CXCR4 expression was confirmed in corneal tissues of patients with CNV and hypoxic HCE-T cells. The supernatant from hypoxia-treated HCE-T cells is involved in the CXCR4-mediated angiogenesis of human umbilical vein endothelial cells. Notably, miR-1910-5p was demonstrated to be at a high level in wild-type HCE-T cells and its supernatant, and in CNV patient tears. The proangiogenic functions of miR-1910-5p were demonstrated with the assays of cell migration, tube formation, and aortic ring. Moreover, miR-1910-5p significantly inhibited multimerin-2 expression by targeting its 3' untranslated region and caused significant extracellular junctional defects in human umbilical vein endothelial cells. MiR-1910-5p antagomir could significantly increase multimerin-2 level and decrease vascular leakage, and ultimately inhibit CNV in a murine model.
Conclusions:
Our results revealed a novel CXCR4-mediated mechanism and proved that targeting the miR-1910-5p/multimerin-2 pathway could be a promising therapeutic target for CNV.
Insights
This study reveals a new mechanism where chemokine receptor 4 (CXCR4) drives corneal neovascularization (CNV) via miR-1910-5p, inhibiting multimerin-2. Targeting this pathway offers a promising therapeutic strategy for CNV.
Area of Science:
- Ophthalmology
- Molecular Biology
- Angiogenesis Research
Background:
- Corneal neovascularization (CNV) is a significant cause of vision loss.
- Chemokine receptor 4 (CXCR4) is implicated in early CNV, but its precise molecular mechanism remains unclear.
Purpose of the Study:
- To elucidate the novel molecular mechanism of CXCR4 in corneal neovascularization (CNV).
- To investigate the role of CXCR4 in related pathological events of CNV.
Main Methods:
- CXCR4 expression analysis via immunofluorescence and Western blotting.
- In vitro assays using human corneal epithelial cells (HCE-T) supernatant and human umbilical vein endothelial cells.
- MicroRNA sequencing, gene interference, and luciferase assays to identify and validate downstream targets.
- In vivo study using an alkali-burned murine model to assess therapeutic interventions.
Main Results:
- Elevated CXCR4 expression observed in CNV patient corneas and hypoxic HCE-T cells.
- CXCR4-mediated angiogenesis confirmed in endothelial cells via HCE-T supernatant.
- miR-1910-5p identified as a key mediator, upregulated in CNV and inhibiting multimerin-2 expression.
- Inhibition of multimerin-2 by miR-1910-5p led to endothelial junction defects and increased vascular leakage.
- Therapeutic inhibition of miR-1910-5p reduced CNV in a murine model.
Conclusions:
- A novel CXCR4-mediated pathway involving miR-1910-5p and multimerin-2 in CNV pathogenesis has been identified.
- Targeting the miR-1910-5p/multimerin-2 axis presents a potential therapeutic strategy for treating corneal neovascularization.
