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Vascular Endothelial Growth Factor-B and The MARKUS RÄSÄNEN RÄSÄNEN MARKUS Recent Publications in this Series 38/2019 Ulrika Julku Prolyl Oligopeptidase and Alpha-Synuclein in the Regulation of Nigrostriatal Dopaminergic Neurotransmission 39/2019 Reijo Siren Screening for Cardiovascular Risk Factors in Middle-Aged Men: The Long-Term Effect of AND REVASCULARIZATION HYPERTROPHY IN CARDIAC KINASE AND THE BMX TYROSINE FACTOR-B GROWTH ENDOTHELIAL VASCULAR Lifestyle Counselling 40/2019 Paula Tiittala DISSERTATIONES SCHOLAE DOCTORALIS AD SANITATEM INVESTIGANDAM Hepatitis B and C, HIV and Syphilis among Migrants in Finland: Opportunities for Public UNIVERSITATIS HELSINKIENSIS Health Response 41/2019 Darshan Kumar Reticulon Homology Domain Containing Protein Families of the Endoplasmic Reticulum 42/2019 Iris Sevilem The Integration of Developmental Signals During Root Procambial Patterning in Arabidopsis thaliana 43/2019 Ying Liu MARKUS RÄSÄNEN Transcriptional Regulators Involved in Nutrient-Dependent Growth Control 44/2019 Ramón Pérez Tanoira VASCULAR ENDOTHELIAL GROWTH FACTOR-B AND Race for the Surface ― Competition Between Bacteria and Host Cells in Implant Colonization Process THE BMX TYROSINE KINASE IN CARDIAC HYPERTROPHY 45/2019 Mgbeahuruike Eunice Ego Evaluation of the Medicinal Uses and Antimicrobial Activity of Piper guineense (Schumach & AND REVASCULARIZATION Thonn) 46/2019 Suvi Koskinen Near-Occlusive Atherosclerotic Carotid Artery Disease: Study with Computed Tomography Angiography 47/2019 Flavia Fontana Biohybrid Cloaked Nanovaccines for Cancer Immunotherapy 48/2019 Marie Mennesson Kainate Receptor Auxiliary Subunits Neto1 and Neto2 in Anxiety and Fear-Related Behaviors 49/2019 Zehua Liu Porous Silicon-Based On-Demand Nanohybrids for Biomedical Applications 50/2019 Veer Singh Marwah Strategies to Improve Standardization and Robustness of Toxicogenomics Data Analysis 51/2019 Iryna Hlushchenko Actin Regulation in Dendritic Spines: From Synaptic Plasticity to Animal Behavior and Human Neurodevelopmental Disorders 52/2019 Heini Liimatta Effectiveness of Preventive Home Visits among Community-Dwelling Older People 53/2019 Helena Karppinen Older People´s Views Related to Their End of Life: Will-to-Live, Wellbeing and Functioning 54/2019 Jenni Laitila Elucidating Nebulin Expression and Function in Health and Disease WIHURI RESEARCH INSTITUTE 55/2019 Katarzyna Ciuba Regulation of Contractile Actin Structures in Non-Muscle Cells TRANSLATIONAL CANCER MEDICINE RESEARCH PROGRAM 56/2019 Sami Blom FACULTY OF MEDICINE Spatial Characterisation of Prostate Cancer by Multiplex Immunohistochemistry and DOCTORAL PROGRAMME IN BIOMEDICINE Quantitative Image Analysis UNIVERSITY OF HELSINKI 57/2019 Outi Lyytinen Molecular Details of the Double-Stranded RNA Virus Replication and Assembly 58/2019 Helsinki 2019 ISSN 2342-3161 ISBN 978-951-51-5404-0 -Vascular Endothelial Growth Factor-B and the Bmx tyrosine kinase in cardiac hypertrophy and revascularization Markus Räsänen Wihuri Research Institute, Translational Cancer Medicine Research Program Doctoral Programme in Biomedicine (DPBM) Faculty of Medicine, University of Helsinki, Finland ACADEMIC DISSERTATION Doctoral dissertation, to be presented for public discussion with the permission of the Faculty of Medicine of the University of Helsinki, in Lecture Hall 2, Biomedicum Helsinki, on the 13th of September, 2019 at 12 o’clock Helsinki 2019 1 1 ISBN 978-951-51-5404-0 (paperback) ISBN 978-951-51-5405-7 (PDF) ISSN 2342-3161 (print) ISSN 2342-317X (online) Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis No. 58/2019 Cover layout by Anita Tienhaara Hansaprint Helsinki 2019 2 2 Supervisors: Kari Alitalo, M.D., Dr. Med. Sci. Research Professor of the Finnish Academy of Sciences Wihuri Research Institute and Translational Cancer Medicine Research Program University of Helsinki Finland Riikka Kivelä, PhD Adjunct Professor, Principal Investigator, Research Fellow of the Finnish Academy of Sciences Wihuri Research Institute and Research Programs Unit University of Helsinki Finland Thesis committee: Ilkka Tikkanen, MD, Dr. Med. Sci Professor Minerva Foundation Institute for Medical Research University of Helsinki Finland Jyri Lommi, MD, Dr. Med. Sci Associate Professor, Chief physician of cardiology Heart and Lung Center Helsinki University Central Hospital Finland Reviewers appointed by the Faculty: Heikki Ruskoaho, MD, Dr. Med. Sci Professor Division of Pharmacology and Pharmacotherapy University of Helsinki Finland Christian Kupatt, Dr. med. Professor 1. Medizinische Klinik, Klinikum rechts der Isar Technical University of Munich Germany Opponent appointed by the Faculty: Kristy Red-Horse, PhD Associate Professor Department of Biology Stanford University 3 3 To my family 4 4 Above all else, guard your heart, for everything you do flows from it. Proverbs 4:23 ‘ 5 5 TABLE OF CONTENTS LIST OF ORIGINAL PUBLICATIONS..................................................................................................... 9 ABSTRACT................................................................................................................................................... 10 REVIEW OF THE LITERATURE ............................................................................................................ 12 Introduction................................................................................................................................................... 12 1. The cardiovascular system and the heart............................................................................................... 12 2. Angiogenesis, VEGF-family and their receptors................................................................................... 14 3. Cardiac development................................................................................................................................ 24 4. Cardiac remodeling in the adult heart.................................................................................................... 29 5. Translational insights of an angiogenic approach to cardiovascular diseases.................................... 32 AIMS OF THE STUDY .............................................................................................................................. 34 MATERIALS AND METHODS ................................................................................................................ 35 RESULTS AND DISCUSSION .................................................................................................................. 44 Study I VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart........................................................................................................... 44 Study II Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling....................................................................................................................... 46 Study III. VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection............................................................................................................................. 50 Study IV VEGF-B promotes endocardium-derived coronary vessel development and regeneration.................................................................................................................................................. 53 CONCLUDING REMARKS ..................................................................................................................... 57 ACKNOWLEDGEMENTS ....................................................................................................................... 61 REFERENCES ........................................................................................................................................... 63 6 6 ABBREVIATIONS AAV (adeno-associated viral vector) αMHC (α-myosin heavy chain) AngII (angiotensin II) Ad (adenoviral) Apln (apelin) CMC/CM (cardiomyocyte) DOX (doxorubicin) EC (endothelial cell) ECG (electrocardiogram) 5-ethynyl-2’-deoxyuridine (EdU) EndMT (endothelial/endocardial-to-mesenchymal transformation) eNOS (endothelial nitric oxide synthase) ERK (Extracellular Signal-regulated Kinase) FDA (The United Stated Food and Drug Administration) HCMEC (human cardiac microvascular endothelial cells) HCAEC (human cardiac arterial endothelial cells) HGF (hepatocyte growth factor) HIF (hypoxia-inducible factor) HUVECs (human umbilical venous endothelial cells) IL (interleukin) KO (knock-out) LEC (lymphatic endothelial cell) LLC (Lewis’ lung carcinoma) MI (myocardial infarction) Nkx2-4 (NK2 homeobox 4) NO (nitric oxide) NRP (neuropilin) PlGF (placental growth factor) PKC (protein kinase C) ROS (reactive oxygen species) 7 7 SDF-1α (stromal cell-derived factor 1 alpha) Sema (semaphorin) sFlt1 (soluble VEGFR-1) Scx (scleraxis) SV (sinus venosus) TAC (transverse aortic constriction) TEC (tyrosine-protein kinase) TG (transgene) TNF (tumor necrosis factor) VEGF (vascular endothelial growth factor A) VEGF-B (vascular endothelial growth factor B) 8 8 LIST OF ORIGINAL PUBLICATIONS The thesis is based on the following original publications. The original publications have been reproduced at the end of the thesis with the permission of the copyright holders. I Kivelä R, Bry M, Robciuc MR, Räsänen M, Taavitsainen M, Silvola JM, Saraste A, Hulmi JJ, Anisimov A, Mäyränpää MI, Lindeman JH, Eklund L, Hellberg S, Hlushchuk R, Zhuang ZW, Simons
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