The Wnt signaling is a complex pathway which is composed of the Wnt protein ligand, membrane receptors, extracellular inhibitory factors, intracellular signal switch and nuclear transcription factors. Wnt signaling has been identified as an essential pathway which is involved in development, tissue regeneration and cancer . Sonderegger et al. analyzed the human Wnt ligands and their receptors in the human placenta, they found that 14 out of 19 Wnt ligands and 8 out of 10 receptors were detectable in human placental tissues . Furthermore, Wnt3A stimulated trophoblast migration and invasion through the matrigel, suggesting that the canonical Wnt pathway may promote invasive of trophoblasts, and the exaggerated activation of the pathway could contribute to trophoblastic hyperplasia and local invasion . In conclusion, recent studies have shown that the Wnt signaling pathway may regulate the processes of implantation and invasion. However, abnormal trophoblast invasion of spiral arterioles is believed to lead to PE. We speculated that undue inhibition of the Wnt signaling pathway in placentas might be involved in the pathogenesis of PE.
β-catenin is considered to be the intracellular signal switch in the canonical Wnt signaling pathway. It has been implicated in the genesis of many human cancers, including non-small cell lung cancer, colorectal carcinoma and many others cancer variants [17–20].
Previous study reported that the β-catenin destabilization could be provoked and trophoblast motility reduced because of the gene silencing of protease activated receptor-1, PAR1 . Moreover, recent studies revealed that nuclear β-catenin expression in a considerable number of invasive trophoblasts in vivo, as well as after in vitro differentiation from chorionic villous explant cultures. Elevated numbers of β-catenin-positive nuclei were detected in the invasive trophoblasts of complete hydatidiform mole (CHM) placenta, suggesting that the abnormal activation of canonical Wnt signaling could play a pivotal role in the gestational disease . Furthermore, early in pregnancy enhanced Wnt/β-catenin signaling is prerequisite for proper implantation and invasion of trophoblast cells . The human placenta undergoes high levels of both angiogenesis and vasculogenesis in pregnancy, the initiation, maturation, and maintenance of the placental vasculature are crucial to the normal pregnancy. However, in the process of the pathogenesis of PE, the major pathological abnormality in the placenta is insufficient maternal spiral artery remodeling, cytotrophoblast cells fail to acquire the endothelial-like phenotype and are unable to invade the myometrial spiral arteries, this failure results in persistent placental hypoxia and dysfunction . The recent study reported that vascular defects appeared in endothelial β-catenin −/− mutants mice, in the placenta of the endothelial β-catenin −/− mutants mice, the labyrinthine layer was reduced in thickness and less vascularized . In this study, the results of immunostaining, real-time PCR and western blot are consistent in that the β-catenin expression was significantly decreased in the severe PE group. Thus, we speculated that the decreased expression of β-catenin may have certain associations with PE. The early placental development requires more maternal blood supply. This requirement is contented with the extensive remodeling of the maternal uterine spiral artery. Vascular remodeling depends on EVT, which has biological similarity to the behavior of tumor cells. However, in PE, the invasion of EVT and the placental circulation amount decreased. The expression of β-catenin in normal trophoblasts is reportedly localized at the membrane and cytoplasmatic compartment . In this study, we observed that β-catenin localized at the syncytiotrophoblast and the EVT in both severe PE and control groups, however, the staining intensity of β-catenin in the placental tissue of the severe PE group was weaker than the normal controls group. However, the exact role of β-catenin requires further functional experiments.
DKK1, the founding member of the dickkopf (DKK) family, plays important roles in diverse developmental processes. It has been implicated in the process of tumorigenesis, such as in the case of colorectal cancer, medulloblastoma, and mesothelioma [26, 27].
Recent studies have suggested that DKK1 may negatively affect the implantation and adhesion of the trophoblast to the endometrium. The treatment of JAR spheroids with DKK1 was shown to impair the attachment to endometrial-like Ishikawa cells . DKK1 has also been reported to decrease the proliferation of cytotrophoblasts in human villous explants . Furthermore, the treatment of primary trophoblasts and SGHPL-5 cells with DKK1 not only abolished Wnt-induced cell motility, but also reduced basal migration and invasion . Our study indicated that DKK1 mRNA and protein expression was significantly increased in the severe PE group, furthermore, the staining intensity of DKK1 was greater in the severe PE group. Dickkopf-1 (DKK1) is a secreted glycoprotein that can antagonize the canonical Wnt signaling pathway, and our study indicated that the expression of DKK1 was increased in the placenta with severe PE, we speculated that the over-expression of DKK1 may have certain associations with PE, and the abnormal state of Wnt signaling pathway might be involved in the the pathogenesis of PE. Moreover, immunohistochemistry results showed that the DKK1 protein was primarily expressed in the syncytiotrophoblast, which is in accordance with previous studies. We also found that DKK1 was localized at the EVT. However, previous study reported that DKK1 was expressed in mice decidual cells , but in this study, we haven’t collect decidual specimen from human, the DKK1 expression in human decidual tissues and the exact role of DKK1 still need further study.
PE is a multisystem disease, the subclassifications of PE are often defined as: mild, moderate, and severe, as well as early and late. The concept of early and late PE is more modern, and it is widely accepted that these two entities have different etiologies and should be regarded as different forms of the disease [31, 32]. In our hospital, we often choose conservative treatment, not cesarean delivery, for the pregnant woman with early- preeclampsia, so there is a limitation in obtaining the placenta tissue of these patients, however, in our future study, we expect that we could obtain variety of specimens including the mother blood and placenta of early and late PE, and do some research on the Wnt signaling in the early and late PE.
Clinical risk factors for intrauterine fetal growth contain severe PE, cardiopulmonary system disorders, umbilical cord and placenta dysfunction, etc. In this study, we also found that the β-catenin expression was decreased, and the DKK1expression was increased in the severe PE group who had an IUGR fetus compared with those with an AGA fetus (P<0.05). However, the results suggested that there is no difference in the expression of β-catenin and DKK1 between patients with preterm and term PE. Potential reasons for this finding may be that the premature birth contains spontaneous premature delivery and therapeutic premature delivery, the influence factors are complex.