Abstract
Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.
Highlights
Tissue samples were taken from placentas within 30 min post-delivery, formalin-fixed and paraffin-embedded (FFPE) for immunohistochemistry staining (IHC), or frozen immediately in liquid nitrogen for mRNA and protein extraction, which were stored at −80 ◦ C until usage
Cell Cycle Regulators Are Affected by the Delivery Mode, and Expressed in Trophoblast Organoids and Placental Tissues
The level of p21 is only reduced in fCTBs of early-onset PE placental tissues and its overall protein expression is decreased in early-onset PE complicated by the HELLP syndrome
Summary
PE is a multisystemic gestational disease with a global prevalence of up to 8% [1] It is characterized by concurrent hypertension and proteinuria or any other sign of end organ damage including liver or brain, occurring after 20 weeks of gestation [2]. PE is a consequence of diverse pathophysiological processes linked to maternal endothelial dysfunction and systemic inflammation, which can result in multiorgan failure, if the fetus and placenta are not delivered [1,2,3]. It can be subdivided into an early-onset (
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