University of Groningen
Fetal programming in pregnancy-associated disorders
Stojanovska, Violeta
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2018
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Stojanovska, V. (2018). Fetal programming in pregnancy-associated disorders: Studies in novel preclinical
models. University of Groningen.
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Stojanovska, Violeta
Fetal programming in pregnancy-associated disorders Studies in novel preclinical models
PhD dissertation, University of Groningen, The Netherlands
Cover design: Violeta Stojanovska, Bregje Jaspers, Proefschriftontwerp.nl Cover image: 8 weeks old fetus; Copyright © Scott Camazine
Layout: Violeta Stojanovska Printed by: Proefschriftmaken.nl ISBN (printed): 978-94-034-0511-7 ISBN (digital): 978-94-034-0510-0 Copyright©2018 Violeta Stojanovska
All rights reserved. No part of this publication may be reproduced, distributed, stored in retrieval system or transmitted, in any form or by any means, without permission of the author and the publisher holding respective copyrights of the published articles, if applicable.
Printing of this thesis was financially supported by the University of Groningen, University Medical Center Groningen, Graduate School of Medical Sciences, Research Institute SHARE.
Fetal programming in
pregnancy-associated disorders
Studies in novel preclinical models
PhD thesis
to obtain the degree of PhD at the
University of Groningen
on the authority of the
Rector Magnificus Prof. E. Sterken
and in accordance with
the decision by the College of Deans.
This thesis will be defended in public on
Wednesday 4 April 2018 at 14:30 hours
by
Violeta Stojanovska
born on 4 February 1986
in Skopje, Macedonia
Supervisor
Prof. S. A. Scherjon
Co-supervisor
Dr. T. Plösch
Assessment committee
Prof. E. Winterhager
Prof. E. A. P. Steegers
Prof. H. J. Verkade
Paranymphs
R. H. Mistry
D. J. Dijkstra
Table of contents
GENERAL INTRODUCTION 9
FETAL PROGRAMMING 10
CRITICAL WINDOWS OF DEVELOPMENT 10
PREGNANCY-ASSOCIATED DISORDERS 11
ANIMAL MODELS OF PREGNANCY-ASSOCIATED DISORDERS 13
OFFSPRING RESPONSE 14
AIM AND OUTLINE OF THE THESIS 17
REFERENCES 19
PREECLAMPSIA AS MODULATOR OF OFFSPRING HEALTH 25
ABSTRACT 26
INTRODUCTION 27
EVIDENCE FROM HUMAN STUDIES: OFFSPRING STATUS AFTER PREECLAMPSIA 28 INTRAUTERINE ADVERSE ENVIRONMENT DURING PREECLAMPSIA AND OFFSPRING OUTCOME:
ANIMAL STUDIES 29
UNDERLYING MECHANISMS OF DEVELOPMENTAL PROGRAMMING 34
CONCLUDING REMARKS 40
REFERENCES 42
IN UTERO SFLT-1 EXPOSURE DIFFERENTIALLY AFFECTS GENE EXPRESSION
PATTERNS IN FETAL LIVER 55
ABSTRACT 56
INTRODUCTION 57
MATERIALS AND METHODS 58
RESULTS 61
DISCUSSION 66
REFERENCES 70
SUPPLEMENTARY FILES 73
A DOUBLE HIT PREECLAMPSIA MODEL RESULTS IN SEX-SPECIFIC GROWTH
RESTRICTION PATTERNS 75
ABSTRACT 76
INTRODUCTION 77
MATERIALS AND METHODS 78
RESULTS 81
DISCUSSION 89
REFERENCES 93
PLACENTAL INSUFFICIENCY CONTRIBUTES TO FATTY ACID METABOLISM
ALTERATIONS IN AGED FEMALE MOUSE OFFSPRING 101
ABSTRACT 102
INTRODUCTION 103
MATERIALS AND METHODS 104
RESULTS 106
DISCUSSION 111
REFERENCES 114
DIABETES IN PREGNANCY LEADS TO GROWTH RESTRICTION AND EPIGENETIC
MODIFICATION OF SREBF2 GENE IN RAT FETUSES 119
ABSTRACT 120
INTRODUCTION 121
MATERIALS AND METHODS 122
RESULTS 124 DISCUSSION 132 PERSPECTIVES 134 REFERENCES 135 SUPPLEMENTARY FIGURES 139 143
GENERAL DISCUSSION AND FUTURE PERSPECTIVES 143
GENERAL DISCUSSION 145
FETAL GROWTH RESTRICTION AS A FETAL PROGRAMMING INDICATOR 145 THE ROLE OF PREECLAMPSIA IN FETAL AND ADULT HEALTH 146 THE IDEAL PRECLINICAL PREECLAMPTIC MODEL TO STUDY FETAL PROGRAMMING 147 THE ROLE OF PLACENTAL INSUFFICIENCY AND INTRAUTERINE GROWTH RESTRICTION IN ADULT
HEALTH 148
THE ROLE OF PRE-EXISTING DIABETES IN FETAL PROGRAMMING 148 PREGNANCY-ASSOCIATED DISORDERS: DO THEY DIFFERENTLY AFFECT THE FETUS? 149 SEX-SPECIFIC DIFFERENCES IN FETAL PROGRAMMING 150 FUTURE PERSPECTIVES:FETAL PROGRAMMING AS A DRUG TARGET 150
REFERENCES 152
APPENDICES 157
SUMMARY 159
NEDERLANDSE SAMENVATTING 163
ACKNOWLEDGMENTS 167
RESEARCH INSTITUTE SHARE 170
PUBLICATION LIST 173
