Abstract
The placenta could transmit information to the maternal circulation via the secretion of small extracellular vesicles (sEVs), but little is known about whether and how these sEVs participate in premature labor (PTL). We speculate that miRNA plays an important role in sEV-mediated fetal-maternal information transmission. The present study was aimed at investigating whether the placenta can regulate the contraction of the maternal myometrium via sEV-mediated transmit of miR-25-3p during PTL. The expression of miR-25-3p and its targets Cav3.2 and SERCA2a in clinical samples, cells, and animal specimens was detected. The role of miR-25-3p was observed in the LPS-induced preterm labor mouse model. The sEVs from HTR-8/SVneo cells were characterized by transmission electron microscopy and nanoparticle tracking analysis. The Ca2+ oscillation in HMSMs was analyzed by an intracellular Ca2+ change tracking assay on a confocal microscope. The contraction of HMSMs was detected by a collagen matrix contraction assay. We found that miR-25-3p can directly bind to the 3′UTR of Cav3.2 and SERCA2a. The miR-25-3p level was decreased, and the expression of its targets Cav3.2 and SERCA2a was increased in the placenta and myometrium tissues of PTL patients. Forced upregulation of miR-25-3p reduced the oxidative stress and inflammation responses and the incidence of PTL in LPS-treated mice. The expression of miR-25-3p was not changed in LPS-stimulated human myometrial smooth muscle cells (HMSMs) but was strongly reduced in the trophoblast cell and its sEVs. Additionally, the trophoblast cell line HTR-8/SVneo could transmit miR-25-3p into HMSMs via sEVs. The sEVs derived from LPS-stimulated trophoblasts upregulated the expression of Cav3.2 and SERCA2a and triggered Ca2+ oscillation as well as the contraction of HMSMs; these effects were partially reversed by the overexpression of miR-25-3p in the trophoblasts. Further, the upregulation of miR-25-3p induced changes of Ca2+ oscillation and contraction of HMSMs mediated by sEVs which were also abrogated by the knockdown of miR-25-3p in HMSMs. The results demonstrated that miR-25-3p plays a crucial role in PTL via Cav3.2- and SERCA2a-mediated Ca2+ oscillation and contraction of HMSMs. PTL seems to be related to the decreased exosomal miR-25-3p content transmitted by the trophoblasts under inflammatory conditions.
Highlights
Births before 37 weeks of gestation are considered premature labor (PTL), which is known as an adverse pregnancy outcome [1]
The present study found that miR-25-3p plays a pivotal role in Ca2+ oscillation and contraction of human myometrial smooth muscle cells (HMSMs) by the regulation of SERCA2a and Cav3.2
We preliminarily revealed the process of PTL: infection changes the composition of a specific miRNA in the trophoblast small extracellular vesicles (sEVs), which twisted the signal transmitted to maternal HMSMs, affected the expression of Cav3.2 and SERCA2a, stimulated Ca2+ oscillation, triggered HMSM contraction, and resulted in PTL
Summary
Births before 37 weeks of gestation are considered premature labor (PTL), which is known as an adverse pregnancy outcome [1]. PTL always has an increased risk of low birth weight, immaturity of multiple organs, serious chronic disabilities (such as respiratory distress syndrome, sepsis, and neurological disorders), or neonatal mortality that affects about 11% of all human newborns [2, 3]. The causes of PTL are complex and varied; oxidative stress, toxin stimulation, placental hypoxia, and immune or endocrine imbalance are all associated with PTL [4]. Infection of the placenta or embryolemma is believed to be the major cause of PTL [5]. The cascade from infection to labor onset and the complex
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