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

Published online by Cambridge University Press:  10 April 2019

V. Stojanovska Open the ORCID record for V. Stojanovska [Opens in a new window] ,
K. M. Holwerda ,
A. M. van der Graaf ,
R. N. Verkaik-Schakel ,
M. V. Boekschoten ,
M. M. Faas ,
S. A. Scherjon  and
T. Plösch
V. Stojanovska
Affiliation:
Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, The Netherlands
K. M. Holwerda
Affiliation:
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
A. M. van der Graaf
Affiliation:
Department of Pathology and Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
R. N. Verkaik-Schakel
Affiliation:
Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, The Netherlands
M. V. Boekschoten
Affiliation:
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, The Netherlands
M. M. Faas
Affiliation:
Department of Pathology and Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
S. A. Scherjon
Affiliation:
Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, The Netherlands
T. Plösch*
Affiliation:
Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, The Netherlands
*
Address for correspondence: Torsten Plösch, Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, PB 30 00, 9700RB Groningen, The Netherlands. E-mail: t.plosch@umcg.nl
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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.

Keywords

animaldevelopmental stageepigeneticsfetusgeneralmolecular/cellularsmall animals
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 10 , Issue 3 , June 2019 , pp. 353 - 361
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2019 

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