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Role of Laeverin in the Pathophysiology of Preeclampsia. —

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Role of Laeverin in the Pathophysiology of Preeclampsia. — Faculty of Health Sciences Department of Clinical Medicine Role of laeverin in the pathophysiology of preeclampsia. Role of laeverin in the pathophysiology of preeclampsia - Mona Nystad in the pathophysiology of preeclampsia Role of laeverin — Mona Nystad A dissertation for the degree of Philosophiae Doctor, May 2018 ISBN 978-82-7589-582-8 ROLE OF LAEVERIN IN THE PATHOPHYSIOLOGY OF PREECLAMPSIA Mona Nystad A dissertation for the degree of Philosophiae Doctor – May 2018 Women’s Health and Perinatology Research Group Department of Clinical Medicine Faculty of Health Sciences UiT – The Arctic University of Tromsø Cover photos Picture of the baby and the placenta on the front page is reproduced with the courtesy of the photographer and midwife Emma Jean (Emma Jean Photography, Brisbane, Australia) and the parents of the baby. Pictures in the lower column are immunofluorescence pictures of trophoblast cells, which are the major constituents of the placenta. Left picture is of cytotrophoblast cells from normal placenta stained with green fluorescence antibodies against laeverin protein (in plasma membrane). Middle picture is of extravillous trophoblast cells of normal placenta stained with red fluorescence antibodies against laeverin (in plasma membrane) and green fluorescence antibodies against cytokeratin 7 protein (in cytoplasma). Right picture is of cytotrophoblast cells from placenta of a preeclampsia patient stained with green fluorescence antibodies against laeverin protein (in cytoplasma). Cells are counterstained with DAPI II (blue) to show the nuclei. EXAMINATION COMMITTEE 1ST OPPONENT Associate Professor (PhD) Marijke M. Faas Department of Pathology and Medical Biology University of Göringen, The Netherlands 2ND OPPONENT Professor (MD, PhD) Anne Cathrine (Annetine) Staff Department of Obstetrics and Gynecology University of Oslo, Norway LEADER OF THE EVALUATION COMMITTEE Professor (PhD) Inigo Martinez Department of Clinical Medicine UiT-The Arctic University of Norway Tromsø, Norway Date of Doctoral Defence: 11th of May 2018 CONTENTS ACKNOWLEDGEMENTS .................................................................................................................................. 5 ABBREVIATIONS ............................................................................................................................................... 7 ABSTRACT ......................................................................................................................................................... 10 ENGLISH VERSION ............................................................................................................................................. 10 NORWEGIAN VERSION ....................................................................................................................................... 11 LIST OF PAPERS .............................................................................................................................................. 12 INTRODUCTION ............................................................................................................................................... 13 GENES AND THE HUMAN GENOME ..................................................................................................................... 13 FERTILIZATION AND EARLY EMBRYO DEVELOPMENT ........................................................................................ 15 TROPHOBLAST CELL BIOLOGY ................................................................................................................ 16 BLASTOCYST IMPLANTATION ............................................................................................................................ 16 TROPHOBLAST DIFFERENTIATION AND FUNCTION ............................................................................................. 17 PLACENTAL MORPHOLOGY AND FUNCTION ....................................................................................... 21 NORMAL PLACENTAL DEVELOPMENT ................................................................................................................ 21 PLACENTAL FUNCTION ...................................................................................................................................... 24 PLACENTA-RELATED DISEASES .......................................................................................................................... 24 PREECLAMPSIA ............................................................................................................................................... 25 HISTORICAL PERSPECTIVES ............................................................................................................................... 25 DEFINITIONS ...................................................................................................................................................... 25 RISK FACTORS ................................................................................................................................................... 26 PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS ....................................................................................... 26 MOLECULAR BASIS ............................................................................................................................................ 27 GENETIC PREDISPOSITION .................................................................................................................................. 29 Family studies and twin studies .................................................................................................................... 29 Paternal impact ............................................................................................................................................ 30 Genes involved in preeclampsia ................................................................................................................... 30 BIOMARKERS OF PREECLAMPSIA ....................................................................................................................... 32 Pro-and anti-angiogenic factors .................................................................................................................. 33 LAEVERIN ......................................................................................................................................................... 34 HISTORY OF LAEVERIN IDENTIFICATION ............................................................................................................ 34 LAEVERIN GENE ................................................................................................................................................ 34 LAEVERIN PROTEIN ........................................................................................................................................... 36 FUNCTION OF LAEVERIN .................................................................................................................................... 39 Enzyme function ........................................................................................................................................... 39 Role of laeverin in trophoblast proliferation and invasion .......................................................................... 40 Expression of laeverin in trophoblast cells and tissues ................................................................................ 40 Role of laeverin in blood pressure regulation .............................................................................................. 41 AIMS OF THE STUDY ...................................................................................................................................... 41 MATERIALS AND METHODS........................................................................................................................ 42 CLINICAL EVALUATION OF PREECLAMPSIA ........................................................................................................ 42 SAMPLE COLLECTION AND CONSERVATION ....................................................................................................... 42 Blood samples .............................................................................................................................................. 43 Placental samples ......................................................................................................................................... 44 1 FIRST TRIMESTER TROPHOBLAST CELL LINE ...................................................................................................... 45 LAEVERIN PROTEIN EXPRESSION ANALYSIS ....................................................................................................... 45 Total protein isolation from placenta ........................................................................................................... 45 Antibodies ..................................................................................................................................................... 46 Western blot analysis.................................................................................................................................... 47 Immunofluorescence ..................................................................................................................................... 48 Immunohistochemistry .................................................................................................................................
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