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Trpv4 Mechanotransduction in Vascular Growth And TRPV4 MECHANOTRANSDUCTION IN VASCULAR GROWTH AND INTEGRITY A dissertation submitted to Kent State University in collaboration with Northeast Ohio Medical University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Holly C. Cappelli February 2017 © Copyright All rights reserved Except of previously published material Dissertation written by Holly C. Cappelli B.S., University of Mount Union, 2012 Ph.D, Kent State University, 2017 Approved by ____________________________, Chair, Doctoral Dissertation Committee Charles K. Thodeti, Ph.D. ____________________________, Members, Doctoral Dissertation Committee William M. Chilian, Ph.D. ____________________________, Liya Yin, M.D., Ph.D. ____________________________, Moses O. Oyewumi, Ph.D. ____________________________ Derek S. Damron, Ph.D. Accepted by ____________________________, Director, School of Biomedical Sciences Ernest J. Freeman, Ph.D. ____________________________ Dean, College of Arts and Sciences James L. Blank, Ph.D. ii TABLE OF CONTENTS LIST OF FIGURES ...........................................................................................................v LIST OF TABLES .......................................................................................................... vii LIST OF ABBREVIATIONS ....................................................................................... viii ACKNOWLEDGEMENTS ............................................................................................ xi CHAPTER I: INTRODUCTION .....................................................................................1 1.1 The Significance of Angiogenesis Research......................................................1 1.2 Angiogenesis ......................................................................................................1 1.2.1 Sprouting versus Non-Sprouting Angiogenesis ..................................2 1.2.2 Molecular Mechanisms .......................................................................5 1.2.2.1 Biochemical Factors.............................................................5 1.2.2.2 Mechanical Factors ..............................................................6 1.2.2.3. ECM, Integrins, and Matrix Proteases ................................7 1.2.2.4 Cell Junction Proteins ..........................................................8 1.2.3 Vessel Remodeling: The Final Step of Angiogenesis .......................10 1.3 Pathological Angiogenesis ...............................................................................11 1.3.1 Tumor Angiogenesis .........................................................................12 1.3.2 Pathological Retinal Angiogenesis ...................................................13 1.3.3 Current Therapies..............................................................................16 1.4. TRPV4 ............................................................................................................17 1.4.1 TRPV4 in Normal Endothelium ......................................................20 1.4.2 TRPV4 in Diseased Endothelium ....................................................25 1.5 Significance of the Present Study ....................................................................29 iii TABLE OF CONTENTS (continued) CHAPTER II: MATERIALS AND METHODS ..........................................................35 CHAPTER III: RESULTS ..............................................................................................48 1. TRPV4-dependent mechanotransduction mediates angiogenesis and vessel integrity in vivo ................................................................................................48 2. The functional significance of TRPV4 in pathological retinal angiogenesis ..57 CHAPTER IV: DISCUSSION ........................................................................................77 Conclusions ............................................................................................................92 Future Directions ...................................................................................................93 REFERENCES .................................................................................................................96 iv LIST OF FIGURES Figure 1. Angiogenic cascade of events..............................................................................3 Figure 2. Sprouting angiogenesis ........................................................................................4 Figure 3. Retinopathy of prematurity ................................................................................15 Figure 4. TRPV4 mediated mechanotransduction in endothelial cells .............................22 Figure 5. TRPV4-dependent mechanotransduction during angiogenesis .........................27 Figure 6. TRPV4 in angiogenic processes ........................................................................31 Figure 7. Schematic representation of oxygen-induced retinopathy .................................45 Figure 8. Absence of TRPV4 results in abnormal angiogenesis with poor vessel integrity in response to varying matrix stiffness in vivo...................................................................51 Figure 9. TRPV4 modulates VE-cadherin localization at cell-cell junctions ...................53 Figure 10. TRPV4 deletion destabilizes tumor vessel integrity, promoting vascular permeability and metastasis ...............................................................................................56 Figure 11. TRPV4 is functionally expressed in retinal endothelial cells ..........................58 Figure 12. TRPV4 is mechanosensitive in the retinal endothelium ..................................60 Figure 13. TRPV4 knockdown induces abnormal tube formation in HuRMECs ............62 Figure 14. TRPV4KO P5 retinas exhibit no vascular differences ....................................65 Figure 15. P7 retinas are comparable between WT and TRPV4KO mice ........................67 Figure 16. TRPV4KO mice display increased vaso-obliteration ......................................70 Figure 17. TRPV4KO mice exhibit unproductive angiogenesis following OIR ..............73 v LIST OF FIGURES (continued) Figure 18. TRPV4KO P17 OIR retinas exhibit poor vessel integrity ...............................74 Figure 19. TRPV4 is required for VE-cadherin junctions in retinal endothelial cells ......76 Figure 20. Schematic showing TRPV4-mediated tumor vessel integrity. ........................80 Figure 21. Proposed mechanism by which TRPV4 mediates VE-cadherin junctions through expression of VEGFR2.........................................................................................95 vi LIST OF TABLES Table 1. List of human primers used to assess TRPV4 expression. .................................47 vii LIST OF ABBREVIATIONS 4-PDD – 4alpha-phorbol-didecanoate AA - Arachidonic acid ACh – Acetylcholine Ang-1 – Angiopoietin-1 Ang-2 – Angiopoietin-2 ANOVA – Analysis of variance ARD – Ankyrin rich domain Asp – Aspartic acid ATP – Adenosine triphosphate bFGF – Basic fibroblast growth factor CD31 – Cluster of differentiation 31 EC – Endothelial cell ECM – Extracellular matrix EDHF – Endothelium-derived hyperpolarizing factor EET – Epoxyeicosatrienoic acid eNOS – Endothelial nitric oxide synthase ERK1/2 – Extracellular regulated kinase 1/2 FGF – Fibroblast growth factor FGFR – Fibroblast growth factor receptor GSK – GSK1016790A GSK2 – GSK2913874 viii H&E – Hematoxylin and Eosin HIF-1 – Hypoxia-inducible factor 1-alpha HuRMEC – Human retinal microvascular endothelial cell HUVEC – Human umbilical vein endothelial cell IB4 - Isolectin IGF – Insulin growth factor LLC – Lewis lung carcinoma cell MAP7 - Microtubule-associated protein 7 Met – Methionine MMP – Matrix metalloproteinases N-cadherin – Neural cadherin NEC – Normal endothelial cell NO – Nitric oxide OIR – Oxygen-induced retinopathy OTRPC4 – Osmosensitive transient receptor potential channel 4 PA – Plasminogen activator PAI – Plasminogen activator inhibitor PDGF – Platelet-derived growth factor PDGFR – Platelet-derived growth factor receptor PECAM – Platelet endothelial cell adhesion molecule PGI2 – Prostacyclin PI(4,5)P2 – Phosphatidylinositol 3,5-bisphosphate PKC – Protein kinase C ix PlGF – Placental growth factor PRD – Proline rich domain ROP – Retinopathy of prematurity SMA – Smooth muscle actin TAF – Tumor associated fibroblast TAM – Tumor associate macrophage TEC - Tumor endothelial cell TEM – Tumor endothelial marker TIMP – Tissue inhibitors of metalloproteinases TRP – Transient receptor potential TRP12 – Transient receptor potential channel 12 TRPV4 – Transient receptor potential vanilloid 4 TRPV4KO – Transient receptor potential vanilloid 4 knockout TRPV4KOEC – Transient receptor potential vanilloid 4 knockout endothelial cell VE-cadherin – Vascular endothelial-cadherin VEGF – Vascular endothelial growth factor VEGFR2 – Vascular endothelial growth factor receptor 2 VRAC – Volume-regulated anion channel VR-OAC – Vanilloid receptor-related osmotically activated channel WT – Wild-type x ACKNOWLEDGEMENTS There are so many people who I want to thank for their help throughout my graduate career because they made it possible for me to achieve this goal of completing my dissertation and Ph.D. First and foremost I would like to express my gratitude and appreciation for my graduate mentor, Dr. Charles Thodeti. He took the time and effort to build trust and establish rapport beyond the usual mentor-mentee
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