Angiopoietin-1/Tie2 Signaling Axis in Endothelial And

Angiopoietin-1/Tie2 Signaling Axis in Endothelial And

ANGIOPOIETIN-1/TIE2 SIGNALING IN ENDOTHELIAL CELLS Sharon Harel McGill University Department of Physiology Montreal, Quebec, Canada August 2016 A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements of the degree of Doctor of Philosophy Sharon Harel 2016 I. ABSTRACT ................................................................................................................ 6 I. RESUME .................................................................................................................... 8 II. ACKNOWLEDGMENTS ........................................................................................ 10 III. LIST OF PUBLICATIONS .................................................................................. 11 IV. CONTRIBUTION OF AUTHORS....................................................................... 12 V. LIST OF ABBREVIATIONS ................................................................................... 13 VI. LIST OF FIGURES .............................................................................................. 19 VII. LIST OF TABLES .................................................................................................... 21 CHAPTER 1: Literature Review ...................................................................................... 22 1.1 Vascular endothelium: structure, function and development ................................. 23 1.1.1 Introduction ...................................................................................................... 23 1.1.2 Structure and function of the vascular endothelium ........................................ 25 1.1.2.1 Structure and function of blood vessels .................................................... 25 1.1.2.2 Structure of the vascular endothelium ...................................................... 26 1.1.2.3 The quiescent endothelium ....................................................................... 27 1.1.2.4 The activated endothelium and inflammation........................................... 28 1.1.2.5 The activated endothelium and angiogenesis ........................................... 30 1.1.3 The formation of blood vessels ........................................................................ 31 1.1.3.1 Vasculogenesis .......................................................................................... 31 1.1.3.2 Angiogenesis ............................................................................................. 32 1.1.3.3 Vessel maturation...................................................................................... 34 1.2 Biological function of Ang-1/Tie-2 axis ................................................................. 35 1.2.1 Pathological angiogenesis and clinical aspects ................................................ 35 1.2.2 Ang-1/Tie-2 in embryonic development (in vivo) ........................................... 37 1.2.3 Ang-1/Tie-2 and in vitro angiogenesis ............................................................ 40 1.2.4 Ang-1/Tie-2 signaling pathways ...................................................................... 40 1.2.4.1 Tie receptors.............................................................................................. 41 1.2.4.2 Angiopoietins ............................................................................................ 44 1.2.4.2.1 Angiopoietin-2 ................................................................................... 45 1.2.4.2.2 Angiopoietin-3/4 ................................................................................ 46 1.2.4.3 The phosphoinositide 3-kinase pathway ................................................... 47 1.2.4.4 NFκB and the inflammatory phenotype .................................................... 49 1.2.4.5 The MAPKs .............................................................................................. 50 1.2.4.5.1 Dual specifity phosphatases as modulators of the MAPKs ............... 55 1.2.4.6 The downstream of kinase related protein pathway ................................. 56 1.2.4.7 The role of integrins in angiopoietin signaling ......................................... 57 2 1.2.4.8 Nuclear modulators of Ang-1/Tie2 induced angiogenesis........................ 58 1. 3 Reactive oxygen species and NADPH oxidase in angiogenesis ............................ 59 1.3.1 Introduction ...................................................................................................... 59 1.3.2 NADPH oxidase: an overview ......................................................................... 60 1.3.2.1 Vascular NADPH oxidase structure, localization and function................ 61 1.3.2.2 Regulation of NOXs in endothelium ........................................................ 63 1.3.2.3 NOX2 and NOX4 in angiogenesis ............................................................ 64 1.3.3 Mitochondrial derived ROS in angiogenesis ................................................... 65 1.3.3.1 Regulation of mitochondrial ROS ............................................................ 66 1.3.3.2 Mitochondrial derived ROS in cell signaling ........................................... 67 1.4.1 Dual role of reactive oxygen species in angiogenesis ..................................... 67 1.4.2 The balance between oxidant and antioxidants ............................................... 68 1.4 MicroRNAs in the regulation of Angiogenesis ...................................................... 70 1.4.1 Discovery of miRNA ....................................................................................... 70 1.4.2 Mechanisms of microRNA biogenesis and silencing by the RNA-induced silencing complex. .................................................................................................... 71 1.4.3 MicroRNAs as modulators of signaling pathways .......................................... 73 1.4.4 MicroRNAs as modulator of Angiogenesis ..................................................... 74 1.4.5 miR-640 ........................................................................................................... 75 1.4.6 ZFP91 ............................................................................................................... 76 1.5 ETS family of transcription Factors in the regulation of angiogenesis .................. 77 1.5.1 ETS’s family of transcription factors an overview .......................................... 77 1.5.2 The Angiopoietin-1/Tie-2 signaling and ETS.................................................. 78 1.5.3 ETS in angiogenesis ......................................................................................... 79 1.6 General objectives and specific aims ...................................................................... 81 Preface to Chapter 2 .......................................................................................................... 82 Chapter 2: NOX2, NOX4 and Mitochondrial-Derived Reactive Oxygen Species (mtROS) Contribute to Angiopoietin-1 Angiogenic Responses in Endothelial Cells ..................... 83 2.1 Abstract ....................................................................................................................... 85 2.2. Introduction ................................................................................................................ 88 2.3 Materials and Methods ................................................................................................ 92 2.4 Results ......................................................................................................................... 97 2.5 Discussion ................................................................................................................ 102 2.6 Acknowledgement .................................................................................................... 110 2.7 References ................................................................................................................. 112 2.8 Figures....................................................................................................................... 118 3 2.9 Figure legends ........................................................................................................... 132 2.10 Tables ...................................................................................................................... 138 Preface to chapter 3 ......................................................................................................... 139 Chapter 3: Regulation of angiogenesis by Angiopoietin-1: Roles of miR-640 and ZFP91 ......................................................................................................................................... 140 3.1 Abstract ..................................................................................................................... 143 3.2 Introduction ............................................................................................................... 144 3.3 Material and Methods ............................................................................................... 146 3.4 Results ....................................................................................................................... 151 3.5 Discussion ................................................................................................................. 158 3.6 Acknowledgments....................................................................................................

View Full Text

Details

  • File Type
    pdf
  • Upload Time
    -
  • Content Languages
    English
  • Upload User
    Anonymous/Not logged-in
  • File Pages
    298 Page
  • File Size
    -

Download

Channel Download Status
Express Download Enable

Copyright

We respect the copyrights and intellectual property rights of all users. All uploaded documents are either original works of the uploader or authorized works of the rightful owners.

  • Not to be reproduced or distributed without explicit permission.
  • Not used for commercial purposes outside of approved use cases.
  • Not used to infringe on the rights of the original creators.
  • If you believe any content infringes your copyright, please contact us immediately.

Support

For help with questions, suggestions, or problems, please contact us