Abstract
Recurrent spontaneous abortion (RSA) is a common health problem that affects women of reproductive age. Recent studies have indicated that microRNAs are important factors in miscarriage. This study investigated the role of miR-16 in regulating vascular endothelial growth factor (VEGF) expression and the pathogenesis of RSA. In this report, clinical samples revealed that miR-16 expression was significantly elevated in the villi and decidua of RSA patients. In vitro, miR-16 upregulation inhibited human umbilical vein endothelial cell proliferation, migration and tube formation. Conversely, the downregulation of miR-16 reversed these effects. In vivo, we demonstrated that abnormal miR-16 levels affect the weights of the placenta and embryo and the number of progeny and microvascular density, as well as cause recurrent abortions by controlling VEGF expression in pregnant mice. VEGF, a potential target gene of miR-16, was inversely correlated with miR-16 expression in the decidua of clinical samples. Furthermore, the luciferase reporter system demonstrated that miR-16 was found to directly downregulate the expression of VEGF by binding a specific sequence of its 3′-untranslated region (3′UTR). Collectively, these data strongly suggest that miR-16 regulates placental angiogenesis and development by targeting VEGF expression and is involved in the pathogenesis of RSA.
Highlights
IntroductionIdentifying a possible mechanism for the regulation of placental angiogenesis might lead to a treatment to combat Recurrent spontaneous abortion (RSA)
Immunohistochemistry revealed that VEGF expression was remarkably lower in Recurrent spontaneous abortion (RSA) patients compared with control pregnant women (Fig. 1A)
We found that the expression of miR-16 in the decidua of the RSA group was significantly greater than that in the decidua of the control group (Fig. 1B)
Summary
Identifying a possible mechanism for the regulation of placental angiogenesis might lead to a treatment to combat RSA. MiRNAs elicit critical changes in gene expression programs that underlie diverse aspects of biology, such as embryogenesis and regulation of cellular differentiation, metabolism, proliferation and apoptosis[14]. An increasing number of studies have demonstrated that miRNAs are expressed abundantly in the human placenta, and dysregulation of miRNAs has been associated with RSA pathogenesis[7,15]. The objectives of the current study were to investigate the expression level of miR-16 in RSA, to evaluate the role of miR-16 on placental angiogenesis both in vitro and in vivo, to provide evidence for the regulation of VEGF expression by miR-16 and to reveal the role this regulation plays in the pathogenesis of RSA (see Supplementary Fig. S1)
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