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Identification of Novel Drivers of Collateral Vessel Remodelling in the Chick Embryo Emily Clare Hoggar

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Identification of Novel Drivers of Collateral Vessel Remodelling in the Chick Embryo Emily Clare Hoggar Identification of novel drivers of collateral vessel remodelling in the chick embryo Emily Clare Hoggar November 2014 A thesis submitted for the degree of Doctor of Philosophy The University of Sheffield Department of Developmental and Biomedical Genetics Acknowledgements I would like to thank my supervisors Dr Tim Chico and Professor Marysia Placzek, whose continued guidance and support has allowed me to develop both personally and professionally as a scientist. Many thanks to my advisors Stephen Renshaw and Anne- Gaelle Borycki who offered both mentorship and advice along the way. I would like to thank the members of both labs for their friendship, knowledge and support over the years. I would also like to acknowledge my parents and Rob who were always there to endure the hard times and celebrate the achievements; I couldn’t have reached the end without you. Statement of contribution The microarray was carried out by Dr Paul Heath in the University of Sheffield Microarray Core Facility. Raw data analysis and normalisation was provided by Dr Marta Milo at the University of Sheffield. Subsequent analysis and interpretation was carried out by myself. HUVECs were kindly acquired and prepared by Marwa Mahmoud and Professor Paul Evans at the Royal Hallamshire Hospital, Cardiovascular Science Department. I performed subsequent QRTPCR and data analysis for these experiments. Particle Image Velocimetry was performed in the lab of Dr Christian Poelma with the help of Astrid Kloosterman at Delft University of Technology. Publications Conference abstracts: Hoggar EC, Placzek M & Chico TJ (2012) FLOW INDUCED VESSEL REMODELLING IN THE CHICKEN EMBRYO IS ASSOCIATED WITH A SPECIFIC GENE EXPRESSION PROFILE. HEART, Vol. 98 (pp A4-A4) Hoggar EC, Placzek M & Chico TJ (2011) TRANSCRIPTIONAL PROFILING REVEALS A REQUIREMENT FOR PHOSPHODIESTERASE 10A DURING FLOW-INDUCED VESSEL REMODELLING IN THE CHICK EMBRYO. HEART, Vol. 97(20) (pp 15-15) 1 | Emily Clare Hoggar Abstract Arterial occlusion accounts for high rates of mortality in the western world. Strategies to bypass an occlusion by activating collateral vessels could reduce the consequences of arterial diseases. This thesis investigates the genes involved in collateral vessel remodelling in the chick embryo to gain insight into the process. Ligation of the right proximal vitelline artery of HH st 17 chick embryos occluded blood flow to the right hand side of the extra- embryonic tissue and vitelline vessel network. Collateral vessels were seen to develop from the pre-existing, left (unligated) vitelline artery and extended across the midline to carry arterial blood to the un-perfused side of the extra-embryonic tissue. The remodelling process was active over 48 hours and developed many small collateral vessels into a few, main conducting arteries. The number of collateral vessels peaked at 12 hours post tied- ligation and then decreased, whilst collateral vessel diameter continued to increase over the time period. Analysis of the global transcriptional profile of collateral vessels in the chick embryo was assessed following ligation, during early stages of collateral vessel development (4 hours), at the point of pruning and remodelling of the collateral network (12 hours). Collateral vessel formation in the chick embryo was found to be associated with a unique and specific gene expression profile. Phosphodiesterase 10A (PDE10A), an cAMP hydrolysing enzyme, was upregulated in tied-ligated embryos at 4 hours post tied-ligation and hypothesised to play a role in the remodelling process. To study PDE10A papaverine hydrochloride was used to inhibit the enzyme. Papaverine had no effect on normal vessel development but significantly impaired collateral vessel diameter from 6 hours post-ligation. This effect was rescued by co-treatment with Protein Kinase A inhibitor, Rp-8-Br-cAMPS. To begin an assessment of the role of PDE10A in collateral vessel remodelling, proliferation was investigated, in vivo. However, a mechanism of action for PDE10A has yet to be elucidated. 2 | Emily Clare Hoggar Table of contents Acknowledgements ................................................................... Error! Bookmark not defined. Statement of contribution ........................................................ Error! Bookmark not defined. Abstract .................................................................................................................................... 2 Table of contents ..................................................................................................................... 3 Table of figures ........................................................................................................................ 7 Table of Tables ....................................................................................................................... 11 Abbreviations ......................................................................................................................... 12 Chapter 1 ................................................................................................................................ 14 Introduction ........................................................................................................................... 14 1.1 Atherosclerosis and the clinical relevance of arterial occlusion ...................................... 14 1.2 Arteriogenesis and the process of collateral vessel remodelling .................................... 15 1.2.1 Collateral vessel architecture........................................................................................ 16 1.2.2 The timecourse of collateral vessel remodelling .......................................................... 16 1.3 Arteriogenesis vs angiogenesis ........................................................................................ 18 1.4 Cellular remodelling in arteriogenesis ............................................................................. 23 1.5 Haemodynamic forces as a stimuli for collateral vessel formation ................................. 24 1.6 How do endothelial cells detect haemodynamic changes? ............................................. 25 1.6.1 Signal transduction of fluid forces ................................................................................ 28 1.6.2 How does stimulation of mechanotransduction pathways result in changes in gene expression? ............................................................................................................................ 29 1.7 Transcriptional changes induced by altered shear stress ................................................ 30 1.8 Therapeutic promotion of arteriogenesis ........................................................................ 33 1.9 Changes in haemodynamic flow can alter endothelial cell arterial/venous identity ...... 38 1.10 Model systems of collateral vessel formation ............................................................... 40 1.11 The chicken embryo as a model system to study flow-induced remodelling ............... 43 1.12 The development of the chicken embryo extra-embryonic vasculature....................... 43 1.13 Chick embryo models to investigate the effects of changes in haemodynamic flow ... 49 1.14 The advantages of using the extra-embryonic vasculature of the chicken embryo to study blood vessels in vivo ..................................................................................................... 51 1.15 Cyclic nucleotide phosphodiesterases ........................................................................... 52 1.15.1 Cyclic nucleotides ........................................................................................................ 53 3 | Emily Clare Hoggar 1.15.2 Protein kinases ............................................................................................................ 53 1.15.3 The phosphodiesterase family .................................................................................... 54 1.16 Phosphodiesterase 10A ................................................................................................. 57 1.16.1 PDE10A function ......................................................................................................... 57 1.16.2 PDE10A mechanism of action ..................................................................................... 58 1.17 Thesis aims ..................................................................................................................... 58 Chapter 2 ................................................................................................................................ 60 Materials and methods .......................................................................................................... 60 Materials ................................................................................................................................ 60 Kits/reagents .......................................................................................................................... 61 Antibodies .............................................................................................................................. 63 2.1 General chick embryo methods ....................................................................................... 64 2.1.1 Storage and incubation ................................................................................................. 64 2.1.2 Developmental stages of the chicken embryo ............................................................
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