AbstractFrom molecules to tissues: characterising the relationship between structure and function in ageing arteriesLucy Anne Walton, The University of Manchester,Degree of Doctor of Philosophy, September 2014Increased arterial stiffness is a predictor of cardiovascular events and mortality across a diverse range of populations. Although gross-mechanical stiffness can be measured in vivo, in order to understand the pathological mechanisms it will be necessary to identify which local micro-structural remodelling events are the prime drivers of altered macro-mechanical function. However, characterisation of arterial structure by conventional histological approaches: i) commonly induces artefacts as a consequence of the sectioning process, ii) provides no insight into the three dimensional structure of the tissue and iii) is performed on unpressurised tissue. This project has set out to address these limitations by developing new micro computed x-ray tomography (micro-CT) methodologies which are capable of visualising the three dimensional structure of rat arteries. This new methodology was then been applied in combination with gross-and micro-mechanical testing and atomic force microscopy imaging to characterise the effects of both intra-luminal pressure and age on arterial structure and function. From these investigations it was clear that micro-CT could readily distinguish discrete tissue sub-structures in paraffin embedded tissues, including skin and arteries and that this imaging approach was compatible with complimentary histological and immunohistochemical analyses. Characterisation of the structure and mechanical function of carotid arteries in aged rats demonstrated localised stiffening in the adventitial layer and a change in the molecular structure of adventitial collagen. The effects of intra-luminal pressure on structure using micro-CT revealed changes in artery cross-sectional area, which suggest the artery wall may be compressible. Investigations into the effects of pressure on the molecular structure of adventitial collagen revealed an increase in periodicity at mean pressure. These findings together demonstrate that the adventitial layer has an important role in the development of arterial stiffness. Micro-CT can reveal novel information that improves our understating of artery structure and how artery structure changes during ageing.