Downregulated low-density lipoprotein receptor-related protein 6 induces the maldevelopment of extravillous trophoblast via Wnt/β-catenin signaling pathway

Abstract

Preeclampsia (PE), a special type of hypertensive disorder complicating pregnancy (HDCP), is highly associated with the migratory and invasive capacity of extravillous trophoblasts (EVTs). Here, we aimed to study the functions of low-density lipoprotein receptor-related protein 6 (LRP6) in PE pathogenesis. A comparative analysis of cellular gene expressions between placenta tissues collected from PE patients and normal pregnant women showed that the expressions of LRP6, β-catenin and matrix metallopeptidases/TIMP metallopeptidase inhibitors (MMPs/TIMPs) ratio in placentas of PE patients were much lower than the normal. Then, we constructed and transfected LRP6 siRNA (siLRP6) and LRP6 overexpression vectors into HTR6/SVneo cells. On the contrary to siLRP6, LRP6 overexpression could significant enhance cell viability, and strengthen the abilities of cell migration and invasion. Importantly, the overexpression of LRP6 could induce the upregulation of MMP-2 and MMP-9 levels, and downregulation of TIMPs. The mRNA and protein levels of β-catenin, an intracellular signal transducer of Wnt signaling pathway, were significantly up-regulated under the effects of LRP6 overexpression. XAV939, a Wnt/β-catenin pathway inhibitor, was introduced to confirm the involvement of Wnt/β-catenin pathway in functions of LRP6. The results of cell viability detection showed that XAV939 could significantly inhibit the positive effects of LRP6 overexpression on cell viability. Taken together, low-expressed LRP6 may be responsible of lower migration and invasion of EVTs and subsequent PE, and the mechanisms show a highly association with Wnt/β-catenin pathway.