MiR-222-3p Inhibits Trophoblast Cell Migration and Alleviates Preeclampsia in Rats Through Inhibiting HDAC6 and Notch1 Signaling.

MiR-222-3p was found to be upregulated in plasma of patients with severe preeclampsia (PE). However, its role in PE progression remains elusive. This study aimed to explore the underlying role and mechanism of miR-222-3p in PE progression. Herein, we verified that miR-222-3p was upregulated and HDAC6 mRNA was downregulated in placentas of PE patients compared with normal pregnant controls as measured by RT-qPCR. And miR-222-3p expression was negatively correlated with HDAC6 mRNA expression in PE patients. HTR8/SVneo trophoblast cells were transfected with miR-222-3p mimic or miR-222-3p inhibitor, and we found that MiR-222-3p overexpression inhibited proliferation, migration, and matrix metalloproteinase (MMP)-2 and MMP-9 levels in HTR-8/SVneo cells, while miR-222-3p silencing showed the opposite results. Online bioinformatics analysis and dual-luciferase reporter assay confirmed that HDAC6 was a target of miR-222-3p. HDAC6 overexpression promoted HTR-8/SVneo cell proliferation and migration, while HDAC6 knockdown suppressed cell proliferation and migration. Moreover, HDAC6 overexpression and Notch1 signaling activation both reversed the inhibitory effects of miR-222-3p on trophoblast cell proliferation and migration. Additionally, treatment with miR-222-3p inhibitor attenuated blood pressure and fetal detrimental changes in PE rats. Collectively, our findings suggested that MiR-222-3p inhibited HDAC6 expression and blocked the Notch1 signaling, thus suppressing trophoblast cell proliferation and migration and attenuating blood pressure and fetal detrimental changes in PE rats, which is expected to become a therapeutic target for PE.