Stimulation of endothelial progenitor cells by microRNA-31a-5p to induce endothelialization in an aneurysm neck after coil embolization by modulating the Axin1-mediated β-catenin/vascular endothelial growth factor pathway

Guo Yu MD, Peixi Liu MD, Yuan Shi MD, Sichen Li MD, Yingjun Liu MD, Zhiyuan Fan MD and Wei Zhu MD, PhD
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  • Department of Neurosurgery, Huashan Hospital of Fudan University, Shanghai, People’s Republic of China
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OBJECTIVE

Emerging evidence shows that frequent recurrence of intracranial aneurysms (IAs) after endovascular coiling is attributable to the lack of endothelialization across the aneurysm neck. Recently, much attention has been given to the role of microRNAs (miRs) in vascular disease, although their contributory role to IA is poorly understood.

METHODS

Adult male Sprague-Dawley rats were subjected to microsurgery to create a coiled embolization aneurysm model, and were injected with miR-31a-5p agomir or a negative control agomir via the tail vein at a dose of 10 mg/kg per week for 4 weeks after IA induction. H & E staining, scanning electron microscopy, and flow cytometry were performed to evaluate the effects of miR-31a-5p agomir on endothelialization and the number of circulating endothelial progenitor cells (EPCs). The effects of miR-31a-5p on the viability and functioning of EPCs were also determined using Cell Counting Kit–8, wound-healing assay, and tube formation assays.

RESULTS

The authors tested the ability of miR-31a-5p to promote EPC-induced endothelialization in a model of coiled embolization aneurysm. miR-31a-5p agomir improved endothelialization and elevated the number of circulating EPCs in the peripheral blood compared to a negative control agomir–treated group. In addition, the number of vWF- and KDR-positive cells in the aneurysm neck was increased in the miR-31a-5p agomir–treated group. Furthermore, upregulation of miR-31a-5p promoted EPC proliferation, migration, and tube formation and enhanced the expression of the proangiogenic factor vascular endothelial growth factor in vitro. Mechanistically, miR-31a-5p directly targeted the 3′ untranslated region (3′UTR) of Axin1 messenger RNA and repressed its expression. Besides, miR-31a-5p exerted its effect on EPCs by regulating the Axin1-mediated Wnt/β-catenin pathway.

CONCLUSIONS

Collectively, these results indicate that miR-31a-5p is an important regulator of EPC mobilization and endothelialization and may have a positive effect on aneurysm repair.

ABBREVIATIONS AN = aneurysm model; EPC = endothelial progenitor cell; IA = intracranial aneurysm; miR = microRNA; mRNA = messenger RNA; mt = mutant; NC = negative control; qRT-PCR = quantitative reverse transcription polymerase chain reaction; SEM = scanning electron microscopy; siRNA = signaling RNA; VEGF = vascular endothelial growth factor; wt = wild type; 3′UTR = 3′ untranslated region.

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Contributor Notes

Correspondence Wei Zhu: Huashan Hospital of Fudan University, Shanghai, People’s Republic of China. drzhuwei@fudan.edu.cn.

INCLUDE WHEN CITING Published online August 9, 2019; DOI: 10.3171/2019.5.JNS182901.

G.Y. and P.L. contributed equally to this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

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