Impaired Wnt5a signaling in extravillous trophoblasts: Relevance to poor placentation in early gestation and subsequent preeclampsia
Introduction
Preeclampsia (PE) is estimated to complicate 2–8% of all pregnancies, and is a leading cause of maternal and neonatal morbidity and mortality [1]. It has been postulated that PE occurs in two stages, i.e. that poor placentation typified by insufficient remodeling of spiral arteries (first stage) results in the release of excessive amounts of placental materials that lead to an excessive maternal inflammatory response and endothelial dysfunction (second stage) [2]. Placentation is a highly complex, regulated process that is crucial for normal fetal growth and the maintenance of a healthy pregnancy. During normal placentation, extravillous trophoblasts (EVT) invade into the decidua and the inner one third of the myometrium [3], [4]. A subset of EVT, i.e. endovascular trophoblasts, invade maternal vessels, disrupt the endothelium and the smooth muscle layer, and replace the vascular wall [3], [4]. These conversions allow spiral arteries to become widely dilated independently of vasomotor control, thereby providing a sufficient blood supply in intervillous space to meet the requirements of the fetus. On the other hand, defective decidual endovascular trophoblast invasion and subsequent impaired spiral artery remodeling are thought to result in less dilated vessels and a lack of adequate placental perfusion, leading to the development of PE [3], [4]. Although early placentation has long been the focus of intense research efforts, the mechanism of impaired spiral artery remodeling has not been fully elucidated.
Accumulating evidence suggests that Wingless (Wnt) signaling plays an important role in placental development and human trophoblast differentiation [5], [6]. Wnt proteins comprise a family of 19 secreted glycoproteins that act as ligands via 12 putative cell-surface receptors and co-receptors [7]. Wnt signaling is a complex pathway that modulates a number of signal transduction pathways and regulates diverse biological functions in a highly cell- and tissue-dependent manner [7], [8], [9]. Wnt signaling is broadly divided into two main categories, i.e. beta-catenin-dependent and beta-catenin-independent signaling. The former signaling pathway regulates target gene expression via beta-catenin stabilization and its translocation to the nucleus, and is closely associated with cell proliferation, cell fate determination, and differentiation [7], [9]. On the other hand, the latter includes activation of c-Jun NH2-terminal kinase (JNK) and protein kinase C (PKC), which regulate cell functions such as cell movement and polarity [7], [8]. Of the 19 known Wnt ligands, 14 have been reported to be expressed in the first trimester placenta [10]. However, the exact role of Wnt ligands in early placentation, especially in spiral artery remodeling, remains controversial. We hypothesized that Wnt signaling is associated with poor placentation and subsequent PE. The aim of this study was therefore to explore the role and underlying mechanisms of Wnt signaling in impaired early placentation and PE.
Section snippets
Microarray data mining for Wnt ligands in early placentation
Publicly available gene expression data of chorionic villus sampling were obtained from the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/gds/) as series matrix files. There was only one data set (GSE12767) that was composed of the first trimester chorionic villi of women who later developed PE (n = 4) and women with unaffected pregnancies (n = 8). Expression values of Wnt ligands were log2 transformed, and probe sets whose maximum expression value across samples was less than 5
Analysis of microarray data reveals Wnt5a as a plausible candidate gene relevant to poor placentation
In order to identify Wnt ligands potentially relevant to early placentation in PE, a total of 25 probes corresponding to Wnt ligand genes, whose maximum expression value across samples was more than 5, were detected in a microarray data set of chorionic villous sampling (GSE12767) that was composed of first trimester chorionic villi of women who later developed PE (n = 4) and women with normal pregnancies (n = 8). Among 25 probes, two probes, both of which represent Wnt5a, showed significantly
Discussion
In this study, we first showed that Wnt5a expression is suppressed in the early placentas of women before developing PE. Moreover, down-regulated Wnt5a was also observed in placentas of PE compared with normal first and term placentas. Furthermore, Wnt5a via PKC and JNK signaling was involved in EVT cell invasion and tube formation. All these findings suggest that dysregulated Wnt5a signaling can be partly attributed to impaired early placentation and the subsequent development of PE.
The
Conclusion
Impaired Wnt5a signaling may be relevant to poor placentation and subsequent PE, and inhibition of Wnt5a/JNK signaling attenuated rhWnt5a-induced invasion and tube formation capabilities. Therefore, modulation of Wnt5a signaling can be a promising therapeutic strategy for the prevention of PE.
Author’s roles
Kondoh E, Matsumura N, and Konishi I designed this study and supervised the project. Ujita M, Chigusa Y, Mogami H, Kawasaki K, Kiyokawa H, Takai H, Sato M, and Kawamura Y performed the in vitro experiments. Ujita M and Kondoh E analyzed data and wrote the paper. Chigusa Y, Mogami H, Horie A, and Baba T edited the manuscript. Mandai M finally approved the version to be published. All authors discussed the results and implications and commented on the manuscript at all stages.
Study funding
Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, and Technology, Japan (No. 26670720).
Acknowledgments
We thank Ms. Teruko Yano for her outstanding secretarial assistance.
Conflict of interest
The authors have no conflicts of interest to declare.
References (25)
- et al.
Pre-eclampsia
Lancet
(2010) - et al.
The “Great Obstetrical Syndromes” are associated with disorders of deep placentation
Am. J. Obstet. Gynecol.
(2011) - et al.
Wnt signaling in implantation, decidualisation and placental differentiation-review
Placenta
(2010) - et al.
Wnt/β-catenin signaling, disease, and emerging therapeutic modalities
Cell
(2017) - et al.
Complex expression pattern of Wnt ligands and frizzled receptors in human placenta and its trophoblast subtypes
Placenta
(2007) - et al.
Differential expression and the anti-apoptotic effect of human placental neurotrophins and their receptors
Placenta
(2011) - et al.
IFPA Senior Award Lecture: making sense of pre-eclampsia – two placental causes of preeclampsia?
Placenta
(2014) - et al.
Wnt5a can both activate and repress Wnt/β-catenin signaling during mouse embryonic development
Dev. Biol.
(2012) - et al.
The two stage model of preeclampsia: variations on the theme
Placenta
(2009) - et al.
The role of the spiral arteries in the pathogenesis of preeclampsia
Obstet. Gynecol. Annu.
(1972)
Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling
Front. Genet.
Wnt signaling and the control of cellular metabolism
Biochem. J.
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