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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
miR-539-5p inhibits experimental choroidal neovascularization by targeting CXCR7
Yifan Feng1, Jing Wang1, Yuanzhi Yuan1
1Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Stromal cell-derived factor-1 (SDF-1) has been previously confirmed to participate in the formation of choroidal neovascularization (CNV) via its receptor, CXC chemokine receptor (CXCR) 4; CXCR7 is a recently identified receptor for SDF-1. The molecular mechanisms and therapeutic value of CXCR7 in CNV remain undefined. In this study, experimental CNV was induced by laser photocoagulation in Brown-Norway pigmented rats, and aberrant CXCR7 overexpression was detected in the retinal pigment epithelial/choroid/sclera tissues of laser-injured eyes. Blockade of CXCR7 activation via CXCR7 knockdown or neutralizing Ab administration inhibited SDF-1-induced cell survival and the tubular formation of human retinal microvascular endothelial cells (HRMECs) in vitro and reduced CNV leakage and lesion size in vivo. By using microRNA array screening and bioinformatic analyses, we identified miR-539-5p as a regulator of CXCR7. Transfection of HRMECs and choroid-retinal endothelial (RF/6A) cells with the miR-539-5p mimic inhibited their survival and tube formation, whereas CXCR7 overexpression rescued the suppressive effect of miR-539-5p. The antiangiogenic activities of the miR-539-5p mimic were additionally demonstrated in vivo by intravitreal injection. ERK1/2 and AKT signaling downstream of CXCR7 is involved in the miR-539-5p regulation of endothelial cell behaviors. These findings suggest that the manipulation of miR-539-5p/CXCR7 levels may have important therapeutic implications in CNV-associated diseases.-Feng, Y., Wang, J., Yuan, Y., Zhang, X., Shen, M., Yuan, F. miR-539-5p inhibits experimental choroidal neovascularization by targeting CXCR7.
Insights
MicroRNA-539-5p targets CXCR7, inhibiting choroidal neovascularization (CNV) by blocking SDF-1 signaling. This discovery offers new therapeutic strategies for treating CNV-related eye diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 are implicated in choroidal neovascularization (CNV).
- CXCR7, another SDF-1 receptor, has undefined roles and therapeutic potential in CNV.
- The molecular mechanisms regulating CXCR7 in CNV require elucidation.
Purpose of the Study:
- To investigate the role and therapeutic implications of CXCR7 in experimental choroidal neovascularization.
- To identify regulatory mechanisms of CXCR7 in the context of CNV.
- To explore the potential of targeting the miR-539-5p/CXCR7 axis for CNV treatment.
Main Methods:
- Experimental CNV was induced in rats via laser photocoagulation.
- CXCR7 expression was analyzed in laser-injured ocular tissues.
- In vitro studies involved human retinal microvascular endothelial cells (HRMECs) and RF/6A cells with CXCR7 knockdown or neutralizing antibodies.
- MicroRNA array screening and bioinformatic analyses identified miR-539-5p as a CXCR7 regulator.
- In vivo studies utilized intravitreal injection of miR-539-5p mimics.
Main Results:
- Aberrant CXCR7 overexpression was observed in laser-induced CNV tissues.
- Blocking CXCR7 inhibited SDF-1-induced endothelial cell survival and tube formation in vitro, and reduced CNV leakage and lesion size in vivo.
- miR-539-5p was identified as a regulator of CXCR7.
- miR-539-5p mimic transfection suppressed endothelial cell survival and tube formation, effects rescued by CXCR7 overexpression.
- The antiangiogenic effects of miR-539-5p were confirmed in vivo.
- ERK1/2 and AKT signaling pathways downstream of CXCR7 were involved.
Conclusions:
- CXCR7 plays a significant role in promoting experimental choroidal neovascularization.
- miR-539-5p acts as an endogenous inhibitor of CXCR7, suppressing CNV progression.
- The miR-539-5p/CXCR7 axis represents a potential therapeutic target for CNV and related diseases.
