In utero sFlt-1 exposure differentially affects gene expression patterns in fetal liver

V. Stojanovska, K.M. Holwerda, A.M. Van Der Graaf, R.N. Verkaik-Schakel, M.V. Boekschoten, M.M. Faas, S.A. Scherjon, T. Plösch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The soluble fms-like tyrosine kinase factor 1 (sFlt-1) is a major contributor to antiangiogenesis during preeclampsia. However, little is known about the effects of sFlt-1 on fetal health. In this study we aim to evaluate the effects of the sFlt-1 concentration during pregnancy on fetal liver physiology. We used adenoviral gene delivery in Sprague-Dawley dams (seven females, 10 weeks old) during mid-gestation (gestational day 8) with adenovirus overexpressing sFlt-1, and age-matched controls (six females, 10 weeks old) with empty adenoviral virus in order to quantify the sFlt-1 concentrations in pregnant dams. Dams exposed to adenoviral sFlt-1 delivery were subdivided into a low (n=4) and high sFlt-1 (n=3) group based on host response to the virus. One-way analysis of variance showed that fetuses (five per dam) exposed to high sFlt-1 concentrations in utero show fetal growth restriction (1.84±0.043 g high sFlt-1 v. 2.32±0.036 g control; mean (M)±s.e.m.; P<0.001), without hypertension or proteinuria in the dams. In continuation, the microarray analysis of the fetal liver of the high sFlt-1 group showed significant enrichment of key genes for fatty acid metabolism and Ppara targets. In addition, using pyrosequencing, we found that the Ppara enrichment in the high sFlt-1 group is accompanied by decreased methylation of its promoter (1.89±0.097 mean % methylation in high sFlt-1 v. 2.26±0.095 mean % methylation in control, M±s.e.m., P<0.02). Our data show that high sFlt-1 concentrations during pregnancy have detrimental effects on the fatty acid metabolism genes and the Ppara targets in the fetal liver.

Original languageEnglish
Pages (from-to)353-361
JournalJournal of Developmental Origins of Health and Disease
Volume10
Issue number3
Early online date10 Apr 2019
DOIs
Publication statusPublished - Jun 2019

Keywords

  • animal
  • developmental stage
  • epigenetics
  • fetus
  • general
  • molecular/cellular
  • small animals

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