Dysfunction of WNT4/WNT5A in deciduas: possible relevance to the pathogenesis of preeclampsia.

Abstract

Preeclampsia affects 5-7% of all human pregnancies worldwide. It is characterized primarily by hypertension and proteinuria. Although the pathogenesis of preeclampsia is still not fully understood, the deficiency in decidualization is considered to have a role in this disease. WNT4 and WNT5A are highly expressed in the deciduas of mice and human beings; their deficiency causes the abnormality of mouse decidualization, and consequently affects the development of the placenta and the fetus. We aimed to define the roles of WNT4 and WNT5A in human decidulization and their relationship with preeclampsia. In this study, we investigated the expression of WNT4 and WNT5A in human deciduas and their functions during decidualization, as well as their relationship with preeclampsia. We obtained deciduas from 20 women whose pregnancies were complicated by severe preeclampsia and from 20 women with uncomplicated pregnancies, as well as human endometrial stromal cells (hESCs). The levels of WNT4 and WNT5A were examined by real-time PCR, immunohistochemistry, and western blotting in deciduas. The expression of WNT4 and WNT5A in cultured hESCs was determined during decidualization. Furthermore, the roles of WNT4, WNT5A, and BMP2 on decidualization as well as their interactions were studied in cultured hESCs by interference of their expression with specific small interfering RNA, respectively. WNT4 and WNT5A were present in the decidual tissues of women with preeclampsia and women with uncomplicated pregnancies. Their expression levels of mRNA and protein in women with severe preeclampsia were significantly lower compared with women with uncomplicated pregnancies (P < 0.05). WNT4 and WNT5A were upregulated in decidualized hESCs. Knocking down of BMP2 or WNT4 in hESCs resulted in a significant increase of WNT5A mRNA and a significant reduction in the transcription of decidualization markers, insulin-like growth factor binding protein1 and prolactin (P < 0.05). In addition, silencing of WNT5A resulted in a reduction of the transcription of insulin-like growth factor binding protein1 and prolactin mRNA (P < 0.05). Our data suggest that WNT4 and WNT5 are relevant to normal decidualization, and thus trophoblast invasion and implantation. Their deficiency is likely involved in the development of preeclampsia.