miR-381-3p contribution in mouse spontaneous abortion via targeting VEGFA

TL;DR

This study identifies miR-381-3p as a key player in mouse spontaneous abortion by inhibiting blood vessel growth through the VEGFA pathway.

Contribution

The novel finding is that miR-381-3p contributes to spontaneous abortion by targeting VEGFA, offering a new therapeutic target.

Findings

miR-381-3p overexpression inhibits migration and angiogenesis of vascular endothelial cells.

miR-381-3p knockdown reduces placental and fetal damage in abortion models via the VEGFA/NF-κB pathway.

VEGFA knockdown reverses the beneficial effects of miR-381-3p inhibition on angiogenesis.

Abstract

Recurrent spontaneous abortion (RSA) affects 1–5% of pregnant women; however, the mechanisms underlying this condition remain unknown. Dysangiogenesis in the placenta is an essential factor in the pathogenesis of RSA. Studies have verified that microRNAs (miRNAs) are vital for RSA; however, their mechanism of action in regulating angiogenesis remains unclear. Therefore, we explored the contribution of key miRNAs that regulate angiogenesis in RSA.

The abortion mouse model was constructed by intraperitoneal injection of beta2-Glycoprotein I (β2-GPI). The abnormal expression of miRNAs in the placenta of the abortion mice was screened using miRNA-seq. Based on miRNA databases, miR-381-3p, which is highly expressed in abortion mice, may bind to vascular endothelial growth factor A (VEGFA). Subsequently, we investigated the effects of the miR-381-3p/VEGFA axis on the angiogenesis of vascular endothelial cells using real-time quantitative polymerase chain reaction, Transwell, wound healing, tube formation, western blotting, and dual-luciferase reporter system. Furthermore, an in vivo experiment was used to confirm miR-381-3p knockdown contribution in the abortion mouse model.

miR-381-3p overexpression inhibited the migration and angiogenesis of C166 cells (a mouse vascular endothelial cell line), whereas miR-381-3p knockdown had the opposite effect. The dual-luciferase reporter system revealed that miR-381-3p bound to the VEGFA 3′ UTR, and VEGFA knockdown counteracted the beneficial effect of the miR-381-3p inhibitor on angiogenesis. An in vivo study demonstrated that miR-381-3p knockdown may reduce inflammation and damage to the placenta and fetus during abortion by activating the VEGFA/nuclear factor kappa B (NF-κB) pathway.

miR-381-3p may cause insufficient placental blood flow by inhibiting the VEGFA pathway and can be used as a potential therapeutic target for RSA.

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