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Primary Human Trophoblasts Mimic the Preeclampsia Phenotype after Acute Hypoxia–Reoxygenation Insult

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Barbara Fuenzalida, Sampada Kallol, Jonas Zaugg, Martin Mueller, Hiten D. Mistry, Jaime Gutierrez, Andrea Leiva, Christiane Albrecht

Original languageEnglish
Article number1898
JournalCells
Volume11
Issue number12
DOIs
Published1 Jun 2022

Bibliographical note

Funding Information: Funding: This study was supported by the Swiss National Science Foundation via the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland (grant no. 51NF40-185544; CA), the Swiss 3R Competence Centre (3RCC; grant no OC-2019-019; CA), and the Lindenhof Foundation, Bern, Switzerland (grant no. 17-15-F; CA). HDM received a British Heart Foundation Basic Science Intermediate Fellowship (FS/15/32/31604). AL and JG received support from the Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT (1190250, 1180935, and 1221362). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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Abstract

Preeclampsia (PE) is a pregnancy-specific disorder that affects 3 to 5% of pregnancies worldwide and is one of the leading causes of maternal and fetal morbidity and mortality. Nevertheless, how these events occur remains unclear. We hypothesized that the induction of hypoxic conditions in vitro in primary human trophoblast cells would mimic several characteristics of PE found in vivo. We applied and characterized a model of primary cytotrophoblasts isolated from healthy pregnancies that were placed under different oxygen concentrations: ambient O2 (5% pCO2, 21%pO2, 24 h, termed “normoxia”), low O2 concentration (5% pCO2, 1.5% pO2, 24 h, termed “hypoxia”), or “hypoxia/reoxygenation” (H/R: 6 h intervals of normoxia and hypoxia for 24 h). Various established preeclamptic markers were assessed in this cell model and compared to placental tissues obtained from PE pregnancies. Seventeen PE markers were analyzed by qPCR, and the protein secretion of soluble fms-like tyrosine kinase 1 (sFlT-1) and the placenta growth factor (PlGF) was determined by ELISA. Thirteen of seventeen genes associated with angiogenesis, the renin–angioten-sin system, oxidative stress, endoplasmic reticulum stress, and the inflammasome complex were susceptible to H/R and hypoxia, mimicking the expression pattern of PE tissue. In cell culture supernatants, the secretion of sFlT-1 was increased in hypoxia, while PlGF release was significantly reduced in H/R and hypoxia. In the supernatants of our cell models, the sFlT-1/PlGF ratio in hypoxia and H/R was higher than 38, which is a strong indicator for PE in clinical practice. These results suggest that our cellular models reflect important pathological processes occurring in PE and are therefore suitable as PE in vitro models.

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