Morphological changes of placental syncytium and their implications for the pathogenesis of preeclampsia

Abstract

Preeclampsia is a hypertensive disease that complicates many pregnancies, typically presenting with new-onset or worsening hypertension and proteinuria. It is well recognized that the placental syncytium plays a key role in the pathogenesis of preeclampsia. This review summarizes the findings pertaining to the structural alterations in the syncytium of preeclamptic placentas and analyzes their pathological implications for the development of preeclampsia. Changes in the trophoblastic lineage, including those in the proliferation of cytotrophoblasts, the formation of syncytiotrophoblast through cell fusion, cell apoptosis and syncytial deportation, are discussed in the context of preeclampsia. Extensive correlations are made between functional deficiencies and the alterations on the levels of gross anatomy, tissue histology, cellular events, ultrastructure, molecular pathways, and gene expression. Attention is given to the significance of dynamic changes in the syncytial turnover in preeclamptic placentas. Specifically, experimental evidences for the complex and obligatory role of syncytin-1 in cell fusion, cell-cycle regulation at the G1/S transition, and apoptosis through AIF-mediated pathway, are discussed in detail in the context of syncytium homeostasis. Finally, the recent observations on the aberrant fibrin deposition in the trophoblastic layer and the trophoblast immature phenotype in preeclamptic placentas and their potential pathogenic impact are also reviewed.

Keywords: HERV-W; Nonfusogenic; Preeclampsia; Pregnancy hypertension; Syncytium.

Fig. 1

Syncytin-1 regulation of syncytium homeostasis. The left panel illustrates that under physiological conditions, or early stage of preeclampsia, low levels of hypoxia and ROS will activate syncytin-1 expression through cAMP and GCMa-mediated pathway. A sufficient level of syncytin-1 leads to upregulation of CDK4, E2F1, and C-Myc, which ensures G1/S transition, promoting cytotrophoblast proliferation. At the same time, syncytin-1 mediates cell fusion and the formation of syncytiotrophoblast and keeps the trophoblast apoptosis at low levels. These actions work together to achieve the syncytium homeostasis, which supports the normal pregnancy. The right panel depicts the pathological situation. High levels of ROS, severe hypoxia, genetic predisposition, or a combination of these factors, may overwhelm the feedback mechanism for upregulation of syncytin-1. At a late stage of preeclampsia, the detrimental factors may affect DNMT expression, leading to hypermethylation and epigenetic silencing of syncytin-1 promoter. An insufficient level of syncytin-1 leads to blocking of G1/S transition, inhibition of trophoblast proliferation, and a reduced cytotrophoblast pool. The low level of syncytin-1 and reduced cell fusion will affect the repair of syncytium. Furthermore, a low level of syncytin-1 causes apoptosis of syncytiotrophoblasts, increases the syncytial deportation, and ultimately, the syncytium deficiency, which contributes to the development of preeclampsia. On the other hand, some preeclamptic conditions may further aggravate the syncytium deficiency, leading to the deterioration of the disease