The role of p53‐MDM2 signaling in missed abortion and possible pathogenesis

• Published in: The journal of obstetrics and gynaecology research Vol. 48; no. 11; pp. 2686 - 2696
• Main Authors: Liu, Ting, Yan, Min, Liu, Fen, Ma, Yuyan, Fang, Yan
• Format: Journal Article
• Language: English
• Published: Kyoto, Japan John Wiley & Sons Australia, Ltd 01.11.2022; Wiley Subscription Services, Inc
• Subjects: Abortion; Angiogenesis; Cell cycle; Correlation analysis; Etiology; Fetuses; Flow cytometry; G1 phase; Hypoxia; Immunohistochemistry; MDM2; MDM2 protein; missed abortion; p53; p53 Protein; Pathogenesis; Polymerase chain reaction; Pregnancy; S phase; Vascular endothelial growth factor
• ISSN: 1341-8076; 1447-0756
• DOI: 10.1111/jog.15385

Background Missed abortion is one of the common obstetrical and gynecological complications, angiogenesis is the most important factor in fetal and placental development. However, the definite etiology and pathogenesis are not fully understood. Methods The mRNA levels of p53, MDM2, VEGF, and HIF‐lα were detected in 60 villous samples of missed abortion patients and 64 healthy controls by quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR). Immunohistochemistry was used to explore the expression and correlation of p53, MDM2, VEGF, and HIF‐lα in villous tissues. Furthermore, we upregulated MDM2 expression in JEG‐3 and BeWo cells under hypoxia, combined with Nutlin3, the cell cycle was determined using flow cytometry and the expressions of p53, MDM2, VEGF, and HIF‐1α were determined by qRT‐PCR and western blot. Results qRT‐PCR demonstrated that the expressions of p53, MDM2, and HIF‐1α were significantly increased and VEGF was decreased in missed abortion group compared with normal pregnancies. Correlation analysis found that p53 was positively correlated with MDM2 and HIF‐1α, and negatively correlated with VEGF in missed abortion group. After administration of Nutlin3, overexpression of MDM2 could arrest cell cycle in G1 phase and reduce the proportion of S phase. The expression of p53 and MDM2 of JEG‐3 cells and BeWo cells which transfected with pcDNA3.1‐MDM2 plasmid were markedly increased after Nutlin3 addition under hypoxic conditions, while the expression of VEGF and HIF‐1α decreased. Conclusion Our data indicated that during the development of villi in early pregnancy, p53‐MDM2 signaling regulate cell cycle and angiogenesis through interaction with HIF‐1α and VEGF, which may be a crucial factor affecting pregnancy outcomes.