Zilmer Johansen, Anne Katrine (2014) Estrogen metabolism in pulmonary arterial hypertension. PhD thesis. http://theses.gla.ac.uk/5199/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Estrogen Metabolism in Pulmonary Arterial Hypertension Anne Katrine Zilmer Johansen BSc (Hons) Submitted in fulfilment of the requirements of the degree of Doctors of Philosophy in the Institute of Cardiovascular and Medical Sciences, University of Glasgow Institute of Cardiovascular and Medical Sciences College of Medical, Veterinary and Life Sciences University of Glasgow ©A.K.Z. Johansen 2014 Author’s Declaration I declare that this thesis has been written entirely by myself and is a record of the work performed by myself, except where acknowledgement has been made. This thesis has not been previously submitted for a higher degree. The research was carried out principally in the Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences at the University of Glasgow under the supervision of Professor Mandy MacLean. All HPLC experiments were carried out in the Queens Medical Research Institute, College of Medicine and Veterinary Medicine at the University of Edinburgh under the supervision of Dr. Ruth Andrew. ii Acknowledgement My PhD has been a wonderful experience and for that I would especially like to thank my supervisor Professor Mandy MacLean. Her extensive support, guidance and the opportunities that she has provided me with have no doubt made this a very fruitful three years. Four years ago I wandered into her office with no idea of what I wanted to do in the future. Today it is very clear and I would not have got here without Mandy. You have been a wonderful supervisor and an inspiration to me. In my final year, we started a fantastic collaboration with Dr. Ruth Andrew from the University of Edinburgh. This was a key part in the success of my research in my final year. Ruth, thank you so much for the knowledge, skills and fantastic supervision that I have received from you. I would also especially like to thank the British Heart Foundation and their sponsors for providing me with the financial support for this research. The MacLean research group have certainly also made this a very positive experience for me on both a professional and personal level. I would especially like to thank my mentor Dr. Kevin White for absolutely everything (including all the pain). You have been an inspiration to me, the best mentor that I could have asked for and I have learnt so much from you. I would also like to give special thanks to Dr. Ian Morecroft, Dr. Kirsty Mair, Ms. Margaret Nilsen and Dr. Yvonne Dempsie for all their support around the lab. Ian and Kirsty, I would especially like to thank you both for your patience and all the time that you devoted to help me with my work. Ian, I miss the weekend singing sessions. And Mags, thanks so much for all your help with immunohistochemistry, your comedian nature and Tuesday olives. Lynn Loughlin has been a lab/cardboard mum, an amazing friend and a colleague. This has been invaluable to me over the past three years. I would also like to thank all my wonderful friends, especially my fellow scientists Emma Wallace, Fiona Greig and Afshan Dean. Emma, you have been the most amazing friend (and colleague) over the years and I have so many good and fun memories with you. Like your mum said, we are so lucky to have found each other. Never forget the Mexicans. Fiona, it didn’t take long for us to realize that we had a lot in common and the need for a wine on a Friday. You are one of my best friends and thank you for always being there for me. And I can only thank Afshan for the many wonderful and disastrous nights at the Corinthian (and beyond). We have certainly had some good times. It has been so amazing to have you here in my final year and I look forward to the many good times ahead. And an especially big thank you goes to Katie iii Stewart, Line Mohr, Denice Albek, Joe Ferguson and Alan Rae for always believing in me and for being such amazing friends. And a big thank you to the girls from 144 - Alex Morris, Morgan Reres, Anna Terje and Kirsteen Bressendorff. And finally, my biggest thank you goes to my wonderful family who have always been so extremely supportive of everything that I do although we are Worlds apart. Mum and Dad, you are just amazing. Thank you so much for all the opportunities that you have given me that has got me where I am today. You have always inspired me and encouraged me to do anything that I wanted to. You are always here for me. And as you would say Dad Insha’Allah. Both the Zilmer and the Johansen have helped me in many ways. Definitely the ying and the yang. My beautiful siblings, Jonas, Sofie, Ida and Jessica you are all my best friends and I just love you. I wish we could all spend more time together. And thanks so much to my amazing acquired family, Jørgen, Ruth and Ted for being the best addition to the family and for truly being family. Og tusind tak til min Danske familie, specielt famse, farfar, Wally, Anne, enkefrue Zilmer og søstre Lene. I har alle spillet en kæmpe rolle i mit liv og har hjulpet mig at nå hertil. Jeg savner jer. Man kan hvad man vil. Anne Katrine Zilmer Johansen iv Table of Contents Author’s Declaration ............................................................................................................. ii Acknowledgement................................................................................................................ iii List of Tables........................................................................................................................ xi List of Figures ..................................................................................................................... xii List of Publications ............................................................................................................ xvi List of Abbreviations and Definitions ............................................................................... xvii Abstract ............................................................................................................................ xxiii Chapter 1 ................................................................................................................................ 1 Introduction ............................................................................................................................ 1 1.1 The pulmonary circulation ...................................................................................... 2 1.1.1 Pulmonary vascular structure and function ...................................................... 2 1.1.1.1 Pulmonary arteries, veins and capillaries ................................................. 3 1.1.2 The function of the pulmonary circulation....................................................... 4 1.1.3 Regulation of blood flow in the pulmonary circulation ................................... 4 1.1.4 Regulation of vascular tone: the endothelium .................................................. 5 1.1.5 Excitation-contraction coupling ....................................................................... 5 1.1.6 Effect of hypoxia on pulmonary vasoconstriction and remodeling ................. 6 1.2 Pulmonary hypertension .......................................................................................... 7 1.2.1 Classification of pulmonary hypertension ....................................................... 7 1.2.2 Pulmonary arterial hypertension ...................................................................... 9 1.2.2.1 Idiopathic and heritable pulmonary arterial hypertension ........................ 9 1.2.2.2 Drug and toxin-induced pulmonary arterial hypertension ........................ 9 1.2.2.3 Associated pulmonary arterial hypertension........................................... 10 1.2.3 The diagnosis, prognosis and epidemiology of pulmonary arterial hypertension ................................................................................................................. 10 1.2.4 Pulmonary arterial hypertension arteriopathy ................................................ 11 1.2.5 The right heart ................................................................................................ 15 1.2.6 Inflammation and pulmonary arterial hypertension ....................................... 15 1.2.7 Treatments ...................................................................................................... 16 2+ 1.2.7.1 Ca channel blockers ............................................................................. 17 1.2.7.2 Endothelin receptor antagonists .............................................................. 17 1.2.7.3 Prostanoids .............................................................................................. 19 1.2.7.4 Phosphodiesterase 5 inhibitors...............................................................