Hypoxia-Inducible Factor 2α (HIF-2α) Impairs Placental Development in Fetal Growth Restriction (FGR)
(2020) 22th annual meeting of the Society for Reproductive Investigation — Location: Vancouver (10.March.2020)
Files
No attached file found for this publication.
Details
- Authors
- et. al.
- Abstract
- INTRODUCTION It is well established that persistent hypoxia in placenta after the 1st trimester of pregnancy leads to preeclampsia and/or FGR. We hypothesize that chronic hypoxia, placental underdevelopment and FGR are intertwined. On the one hand, pathological placentas have shown decreased syncytialization markers. On the other hand, hypoxia impairs in vitro term cytotrophoblast (CT) syncytialization (SCT). HIFs are widely implicated in cellular processes, but their role in placental development after the 1st trimester remains largely unknown. OBJECTIVE To study the anti-fusion effects of HIF-1α and/or HIF-2α on trophoblast SCT and their expression in FGR-placentas. METHODS Villous CTs were extracted from normal term placentas after elective cesarean section (N=5) and cultured under 21% O2 or 2.5% O2 conditions. The expression of HIF-1α and HIF-2α was reduced using specific siRNAs. Complementarily, BeWo and JEG3 cells were transfected with an expression vector coding for a mutant oxygen-resistant HIF-2α and treated with Forskolin, an inducer of SCT (n=6). The effects on the fusion index, SCT markers (βHCG, TWIST1, GCM1, syncytin-2) and the angiogenic balance (sFlt-1/PGF) were assessed by immunofluorescence (IF), RT-qPCR, WB, and ELISA. HIF-1α and HIF-2α expression was quantified in the syncytium of human placentas from FGR fetus (N=12) with VisioPharm®. Results were compared to the control group using 2way ANOVA and Dunnett's multiple comparisons test. RESULTS Reducing HIF-2α expression under 2.5% O2 increased the formation of the syncytium (fusion index: +9.80%, P<0.05) and enhanced CT biochemical differentiation (free βHCG: +281%, P<0.05) as well as the expression of SCT markers TWIST1 (2.96, P<0.001), GCM1 (3.23, P<0.001) and syncytin-2 (1.73, P<0.05). Silencing HIF-2α restored the angiogenic balance, namely increased PGF biodisponibility under 2.5% O2 (sFlt-1/PGF: -72%, P<0.001). Conversely, altering HIF-1α expression had no significant impact on SCT. In cell lines, overexpressing HIF-2α inhibited the SCT of BeWo (free βHCG: -104%, P<0.05) but not of JEG3, since the latter cells lost their ability to form SCTs. At last, histological analyzes showed more HIF-2α-positive nuclei in the syncytium of FGR-placentas (5.02% vs. 16.64%, P<0.001) but no difference regarding HIF-1α. CONCLUSION HIF-2α decreases the fusion of CTs and alters the angiogenic balance. Its overexpression in FGR underlines the importance of understanding its role in SCT in abnormal placentas. Furthermore, targeting HIF-2α could be considered as a therapeutic option for FGR.
- Affiliations
Citations
Colson, A., Depoix, C., Hubinont, C., Sonveaux, P., Debiève, F., & et al. (2020). Hypoxia-Inducible Factor 2α (HIF-2α) Impairs Placental Development in Fetal Growth Restriction (FGR). 22th annual meeting of the Society for Reproductive Investigation, Vancouver. https://hdl.handle.net/2078.5/247757