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Lymphangiogenic Signaling in the Epicardium

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Lymphangiogenic Signaling in the Epicardium LYMPHANGIOGENIC SIGNALING IN THE EPICARDIUM by GANGA HASINI KARUNAMUNI Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr Michiko Watanabe Department of Anatomy CASE WESTERN RESERVE UNIVERSITY January 2011 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. DEDICATION To Charles Palihawadena, my grandfather and role model, my guiding light, and the best person I ever knew To my parents and brother, who have always encouraged me and given me so much love and support 1 TABLE OF CONTENTS LIST OF TABLES…………………………………………………...………................. 5 LIST OF FIGURES………………………………………………. ...………................. 6 ACKNOWLEDGEMENTS…….……...………………………………………............. 9 LIST OF ABBREVIATIONS………………………………………………................ 11 ABSTRACT………………………………………………………………………......... 14 CHAPTER 1: BACKGROUND…………………………………………………........ 16 Historical Perspective on the lymphatics………………....…...……………... 16 The Function and Morphology of the lymphatics………...…..……………... 16 Lymphatic Markers…………………………………………………………… 17 Origins of the Lymphatic System…………..………………………………… 19 Formation of the Lymphatic System in Mammals…….……...…………….. 21 Lymphatic Gene Knockout Models…...………...…...…………….…............ 22 Lymphangiogenic Factors and Receptors…...………………………………. 25 Clinical Significance of the Lymphatics……….…………………….……...... 30 The Lymphatics of the Heart...………………………………………….......... 33 Statement of Purpose………………………………………………………...... 36 CHAPTER 2: Expression of lymphatic markers during avian and mouse cardiogenesis……………………………………………….……………………………52 Abstract…………………………………………….……………………........... 52 Introduction……………………………………….………………………........ 54 Materials and Methods………………………….……………………….......... 57 Results…………………...………………………………………………........... 61 The formation of the Prox-1-positive epicardial lymphatic network in quail…...…………………………………………………………...... 61 Co-localization of Prox-1 with other lymphatic markers in 2 mouse...……………………………………………………………......... 63 Lymphatic markers in epicardial cells in vitro…….………………........ 65 Prox-1 Western Blots....……………………………………………........ 65 Discussion……………...………………………………………..………........... 67 The three sets of cardiac cells with lymphatic phenotype……………..... 67 The lymphangiogenic potential of the epicardium…...………………..... 71 Summary…………………………….................................................................. 72 CHAPTER 3: Activation of epicardial cells by VEGF-C signaling………............. 100 Abstract……………………………………………………………….............. 100 Introduction…………………………………………………………............... 102 Materials and Methods……………………………………………................. 104 Results………………………………………………………………................ 108 Lymphatic progenitors are present in the epicardium…........................ 108 VEGF-C induced Prox-1 nuclear accumulation ex vivo via the VEGFR-3 pathway…….…..................................................................... 109 VEGF-C specifically induced Prox-1 nuclear accumulation in the adult epicardium…................................................................................. 110 The MEK inhibitor UO126 blocked Prox-1 nuclear accumulation both in vitro and ex vivo......................................................................... 112 Discussion…………………………………………………………….............. 113 Summary……………………………............................................................... 115 CHAPTER 4: SUMMARY, SUPPLEMENTARY DATA AND FUTURE DIRECTIONS……………………………….………………………………….......... 139 Summary……………………………………………………………................ 139 The lymphatic network of the embryonic and adult heart……….......... 139 The epicardium as a source of lymphatic cells………………….…...... 141 Supplementary Data…………………………………………………............. 143 3 Oxygen tension and the epicardial lymphatics…………………........... 143 HIF-1 and Prox-1…………………………………………..…............. 146 TCDD and its effect on Prox-1 protein levels………....…………......... 149 Genes regulated by Prox-1 in the epicardium…...…………………............. 152 Future Directions…………………………………………………….............. 154 Final Words…………………………………………………………............... 156 REFERENCE LIST…………………………………………………………….......... 170 4 LIST OF TABLES Table 3-1. Prox-1 nuclear accumulation in the ARECs at different time points of VEGF-C treatment.......................................................................................................... 137 5 LIST OF FIGURES Figure 1-1. Model for the differentiation of the mammalian lymphatic vasculature........ 38 Figure 1-2. Prox-1 expression in the mouse embryo.……………………………........... 40 Figure 1-3. The thoracic duct and the right lymphatic duct.…………..………............... 42 Figure 1-4. The VEGF Family.………………................................................................. 44 Figure 1-5. Branching patterns of the lymphatic vasculature in the adult heart (as determined by dye injection studies)................................................................................ 46 Figure 1-6. The proepicardial organ (arrow) in an HH stage 17 chick embryo................ 48 Figure 1-7. Tracing the path of the proepicardial organ................................................... 50 Figure 2-1. Lymphatic markers in the early quail embryonic heart................................. 74 Figure 2-2. Lymphatic markers in the septated quail embryonic heart............................ 76 Figure 2-3. Diagram of the progressive development of the Prox-1-positive lymphatic network in the avian embryonic heart from HH Stage 24 to 38....................................... 78 Figure 2-4. Prox-1 immunofluorescence in quail heart sections...................................... 80 Figure 2-5. Lymphatic markers in the ED 9.5 mouse heart.............................................. 82 Figure 2-6. Prox-1 and LYVE-1/CD44 were initially not co-localized in the mouse or chick embryo heart............................................................................................................ 84 Figure 2-7. Confocal microscopy of LYVE-1-positive cells (green) in the ED 13.5 mouse heart (441X magnification)…........................................................................................... 86 Figure 2-8. Lymphatic markers in the ED 15 mouse heart............................................... 88 Figure 2-9. Lymphatic markers in the adult mouse heart................................................. 90 Figure 2-10. LYVE-1 and CD31/PECAM co-localization in adult mouse heart sections.............................................................................................................................. 92 6 Figure 2-11. Diagram of the three different types of cells/vessels with lymphatic phenotype in the mouse heart arranged according to location.......................................... 94 Figure 2-12. Lymphatic markers in vitro.......................................................................... 96 Figure 2-13. Prox-1 Western Blots................................................................................... 98 Figure 3-1. Prox-1 staining in ED 16.5 sections of WT1-cre mice…………………….117 Figure 3-2. LYVE-1 staining in ED 16.5 sections of WT1-cre mice…………………..119 Figure 3-3. VEGF-C treatment in explanted hearts for 30 minutes…………………….121 Figure 3-4. Adult rat epicardial cells (ARECs) with FGF, VEGF-C and VEGF-A treatment for 24 hours…………………………………………………………………..123 Figure 3-5. Adult rat epicardial cells treated with VEGF-C for 30 minutes……………125 Figure 3-6. Comparing Prox-1 protein levels via Western Blot………………………..127 Figure 3-7. Adult rat epicardial cells treated with nuclear export inhibitor leptomycin B for 2 hours……………………………………………………………….129 Figure 3-8. The MEK inhibitor UO126 induced a down-regulation of Prox-1 in the nucleus………………………………………………………………………………….131 Figure 3-9. Smooth muscle actin and phallodin staining in DMSO/UO126 and VEGF-C-treated ARECs………………………………………………………………..133 Figure 3-10. The effects of inhibiting VEGFR-3 activation in quail hearts in vivo…....135 Figure 4-1. The lymphatics and coronary arteries in the HH stage 30 quail heart......... 158 Figure 4-2. Myocardial vessels with venous and lymphatic phenotype in the adult mouse heart……………………………………………………………......................... 160 Figure 4-3. Comparison of great vessel lymphatics in normoxic and hyperoxic avian embryonic hearts................................................................................................... 162 7 Figure 4-4. Comparison of ventricular lymphatics in normoxic and hyperoxic avian embryonic heart..................................................................................................... 164 Figure 4-5. Comparison of Prox-1 protein levels under hypoxic and hyperoxic conditions in the developing heart.................................................................................. 166 Figure 4-6. Comparison of Prox-1 protein levels with TCDD exposure in the developing heart.............................................................................................................
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