VU Research Portal Targeting the Cause, affecting the Course de Raaf, M.A. 2016 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) de Raaf, M. A. (2016). Targeting the Cause, affecting the Course: Characterization and Optimization of Experimental Models for Pulmonary Arterial Hypertension. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 29. Sep. 2021 Targeting the cause affecting the course the cause Targeting Characterization and Optimization of ExperimentalCharacterization Arterial Hypertension Models Pulmonary for Targeting the cause affecting the course Characterization and Optimization of Experimental Models for Pulmonary Arterial Hypertension Pulmonary Arterial Hypertension is a progressive and devastating disease char- acterized by dysfunction and remodeling of the pulmonary vasculature, lead- ing to increased pulmonary vascular resistance, compensatory right ventricu- lar remodeling and eventually dilatation and heart failure. To find an effective treatment for Pulmonary Arterial Hypertension, animal models are used to M.A. De Raaf M.A. simulate the disease. In this thesis, Michiel Alexander de Raaf and colleagues describe and character- ize the disease progression of such animal model; the Sugen Hypoxia model. Several treatments were tested and evaluated on their efficacy. As both lungs and heart use mutual pathways for disease progression as well as for compen- satory remodeling against the disease, the treatment paradox ‘what might be beneficial for the lungs, could harm the right ventricle’ was evaluated. Michiel Alexander de Raaf CHAPTER # 2 CHAPTER TITLE Targeting the cause affecting the course Characterization and Optimization of Experimental Models for Pulmonary Arterial Hypertension “The real voyage of discovery is not in seeking new landscapes, but in having new eyes.” M. Proust 1871-1922 cover design ‘the landscape’: modified from microscopy photo of an advanced Sugen Hypoxia lung 3 CHAPTER # ISBN: 978-94-6233-267-6 Awesome cover and thesis design: Pascal Vleugels Printed by: Gildeprint Copyright © 2016 by Michiel Alexander de Raaf All rights reserved. No part of this thesis may be reproduced, stored, or transmit- ted to any form or by any means, without written permission of the author. 4 CHAPTER TITLE VRIJE UNIVERSITEIT TARGETING THE CAUSE, AFFECTING THE COURSE Characterization and Optimization of Experimental Models for Pulmonary Arterial Hypertension ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op dinsdag 24 mei 2016 om 9.45 uur in de aula van de universiteit, De Boelelaan 1105 door Michiel Alexander de Raaf geboren te Breda 5 CHAPTER # promotor : prof.dr. A. Vonk Noordegraaf copromotor : dr. H.J. Bogaard 6 CHAPTER TITLE Cordially dedicated to Paola Ballario la mamma scientifica 7 CHAPTER # Overige leden Promotiecommissie: prof.dr. R. Berger prof.dr. N.F. Voelkel prof.dr. W. Mooi dr. J. Aman dr. M. Kool dr. D. Merkus Financial funding: Grant support was received from PAH patient association “Live Life Max” the Dutch Lung Foundation (Longfonds #3.3.12.036), European Respiratory Society Long Term FellowShip grant 2015 Contract research with Boehringer Ingelheim GmbH We acknowledge cordially “Stichting PHA Nederland” for their financial support to print this thesis. Please visit http://www.pha-nl.nl/ for their dedicated work to Dutch P(A)H patients. We acknowledge “DataSciences International” for their financial support to print this thesis. We acknowledge Mieke van Schaik-Verlee and the late Cor van Schaik for their financial support to print this thesis. The research conducted was performed at: VU University & VU University medical center, Amsterdam, The Netherlands Radboud University medical center, Nijmegen, The Netherlands University Medical Center, Groningen, The Netherlands Virginia Commonwealth University, Richmond, Virginia, USA INSERM UMR_S999, Centre Chirugical Marie Lannelongue, Le Plessis-Robin- son/Paris, France 8 CHAPTER TITLE “We choose to go to the moon. We choose to go to the moon in this decade and do the other things, not because they are easy, but because they are hard, because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win, and the others, too.” John F. Kennedy, September 12, 1962, Rice University, Houston, TX, USA. 9 CHAPTER # 10 CHAPTER TITLE Table of contents Chapter 1: Pulmonary Arterial Hypertension and the evolution of animal models 13 Chapter 2: Reversibility and vascular remodeling in SuHx. 29 Chapter 3: Sugen Hypoxia in 5-HT transporter knock-out rat 57 Chapter 4: Angio-obliterative lesions in the Sugen plus pneumonectomy model. 89 Chapter 5: Evaluation of HDAC inhibitors as treatment for PAH 113 Chapter 6: Tyrosine Kinase Inhibitor BIBF1000 in right ventricular pressure overload 131 Chapter 7: Nintedanib in the Sugen Hypoxia model 153 Chapter 8: ET-1 and ERA in fetal development and PAH 169 Chapter 9: Discussion 189 Chapter 10: Acknowledgements 201 Curriculum vitae 206 Serving science for generations 207 Publication list 208 Received grants and awards 210 Presentations 211 11 CHAPTER # 12 Chapter 1: Pulmonary Arterial Hypertension and the evolution of animal models Pulmonary Arterial Hypertension and the evolution of animal models Chapter 1: Advances in understanding of pulmonary arterial hypertension and the evolution of experimental pulmonary hypertension models. Michiel Alexander de Raaf1,2, Norbert F. Voelkel3, Harm Jan Bogaard1,2 Parts of this chapter were published as: PVRI Chronicle 2015; vol2, issue 2, p55-61 Affiliation: Departments of 1Pulmonology and 2Physiology, VU University Medical Center / Institute for Cardiovascular Research, Amsterdam, The Netherlands. 3Pulmonary and Critical Care Medicine Division, Virginia Commonwealth University, Rich- mond, Virginia, USA. 13 CHAPTER 1 “Primary Pulmonary Hypertension has been called the cardiologist’s cancer” Greg Elliott in personal conversation with Norbert Voelkel, early 80’s 14 Pulmonary Arterial Hypertension and the evolution of animal models Pulmonary Arterial Hypertension (PAH) can be a rapidly progressive and dev- astating disease characterized by dysfunction and remodeling of the pulmonary vasculature, leading to increased pulmonary vascular resistance. The increased vascular resistance pushes the right ventricle (RV) into adaptive compensatory remodeling by hypertrophy, but eventually RV dilatation, heart failure and death of the patient become inevitable [1, 2]. Today, 3 pathways are targeted in PAH treatment: the nitric oxide-cyclic guanosine monophosphate pathway, the endo- thelin pathway and the prostacyclin pathway [3]. Although treatments affecting these pathways delay disease progression and increase survival rates [3, 4], they do not cure PAH [3]. The pathogenic paradigm of PAH has shifted from pulmonary vasoconstriction driven by smooth muscle cells to vascular remodeling affecting all vessel wall layers. In this chapter, a brief overview will be given of how PAH research has converged on the role of the endothelial cell (EC). Due to the appre- ciation of the central role of the EC in both pathogenesis and pathobiology, an- imal models, like the Sugen hypoxia (SuHx) rat model, resembling EC vascular remodeling were developed. However, the SuHx rat model was not characterized and formed the basis for this thesis. In respect to the intima remodeling observed in the SuHx model, several treatments targeting endothelial proliferation were tested in the model. 15 CHAPTER 1 he first WHO classification of Pulmonary Hypertension took place in 1972, Tfollowing on the first attempts of morphologic characterizations of the pul- monary hypertensive lung, for example by Wagenvoort et al. [5, 6], followed by the first WHO classification of Pulmonary Hypertension in 1972. In this classi- fication, the pathological focus in PAH, then called Primary Pulmonary Hyper- tension, was on the vascular media of the pulmonary arterioles, featuring hyper- trophied and hyperplastic pulmonary artery smooth muscle cells (PASMC) [1, 2, 7]. The “vascular media paradigm” of PAH ascribed a major pathogenic role to sustained pulmonary vasoconstriction and was fueled by two PAH outbreaks related to the use of the appetite suppressants Aminorex (Menocil®) and fenflu- ramine (Ponderal®) in the late 60’s and 80’s. Both drugs are serotonin transport- er substrates acting on the PASMC