An investigation into the migration and proliferation of human venous smooth muscle cells in intimal hyperpasia in vein grafts

This thesis examines the role of intimal hyperplasia (IH) in vein bypass grafts and possible strategies to reduce it. Chapters 1 describes the clinical aspects of vein grafts and concentrates on their use in lower limb arterial reconstruction and coronary artery bypass grafts. Chapter 2 reviews the current understanding of the vascular biology of IH with particular emphasis on the roles of smooth muscle cell migration and proliferation. The importance of the role of matrix metalloproteinases in the vascular wall is also described. Methods The following two chapters describe experimental methods. Chapter 3 reviews established experimental methods for the study of IH as established and practised in the department of surgery. Chapter 4 details the development of new techniques for the study of human venous smooth muscle cell migration. This starts with validation of the Boyden migration model with optimisation of parameters for human venous smooth muscle cells, followed by the development and validation of a laboratory model for migration through an extracellular matrix replicant called Matrigel . The final part of this chapter details the testing of a novel fluorescent labelling and automated counting technique for cell migration. The experimental models are then used in testing the compounds, doxycycline, marimastat and simvastatin, in relation to their effects on the processes of migration and proliferation. Results The results showed that Doxycycline affected chemoinvasion at all test doses and proliferation at higher doses but had no effect on simple migration. Marimastat was found to reduce chemoinvasion at higher doses, but not simple migration or proliferation at any of the three doses tested. Simvastatin affected chemoinvasion at all doses but did not affect simple migration or proliferation. In the final chapter, the results are summarised and possible future work arising from this thesis is discussed.