Improving the outcome of interventional procedures

My research centres on the study of vascular pathologies and therapy aimed at improving the outcome of interventional procedures such as vein grafting, balloon angioplasty and stent implantation. With the high prevalence of diseases such as atherosclerosis and peripheral vascular disease in the developed world, as well as the rise in diabetes which predisposes individuals to cardiovascular disease, this area of research is highly topical and likely to remain so for the foreseeable future.

Inflammation and vascular disease
We are investigating the effect of modified lipids and their involvement in neointima formation in the mouse. These lipids are formed by the action of myeloperoxidase in inflamed vessel walls and may contribute to changes in smooth muscle cell proliferation and migration. We are using a mouse wire injury model to assess effects on smooth muscle proliferation and migration and vessel histology. In collaboration with Dr Corinne Spickett and Dr Andy Pitt (Aston University) we can analyse the chlorination of lipids and synthesise lipids required for the project.

Another area of interest is in vein grafting and we have refined a model to study this. We have studied the time course of neointimal hyperplasia and the role of iNOS in driving this response and are currently investigating the role of mast cells in neointimal hyperplasia. For this we have been using a mast-cell deficient mouse and developed a double knockout on the ApoE atherosclerotic background. In collaboration with Professor Andrew Baker we are also using this model to investigate the role of microRNAs (MiRs) in vein grafting.

Stent based drug delivery
The vast majority of angioplasty procedures now involve implantation of a stent. Local delivery of drugs coated onto the stent is an attractive strategy to limit in-stent regrowth and re-narrowing of the vessel. In addition to an in vitro model of stenting which we have used to measure electrical impedance using the stent itself, we have a rabbit and a pig model of in vivo stenting which are both currently in use. In collaboration with Professor Andy Baker (Glasgow University), we are working to load stent with adenovirus which will then be used to carry therapeutic agents into the vessel wall. We have also tested a number of therapeutic interventions given orally (Figure 1- effect of oral MCP-1 inhibitor Bindarit on neointima area (right) compared to animals given no treatment) or via local, stent-based delivery. We are also interested in what causes late-stent thrombosis (see figure2: A –pig heart, B&C- stent showing thrombus in lumen) and whether we can develop compounds which encourage endothelial regrowth following stent implantation.

Endocannabinoids and cardioprotection
In collaboration with Professors Nigel and Susan Pyne (University of Strathclyde) we have been investigating the link between cannabinoids and sphingosine derivatives in the rat coronary artery. A successive PhD studentship and 2year project grant have yielded a huge body of data in this area which we published recently (Mair et al 2010). Endocannabinoids have a cardioprotective function but the mechanism of action is not fully understood. We reviewed the evidence for S1P mediating the cardioprotective effects of cannabinoids recently (Kennedy et al 2009) and we hope to advance this work using mouse knockouts to establish if the endocannabinoid/S1P mechanism can mediate cardioprotective effects in ex vivo hearts.

AMPK and vascular pathology
In collaboration with Dr Ian Salt (Glasgow University) and Dr Marie-Ann Ewart, we are investigating AMPK expression and function in atherosclerosis, with plans to extend this to diabetic and in-stent restenotic tissue. We are interested in how AMPK expression and function changes as atherosclerosis develops and how it may be involved in calcium regulation within the vascular smooth muscle cells. We also intend to study the changes in the biochemical pathways in response to AMPK activation as atherosclerosis develops in the mouse and also to use cultured vascular cells from normal and diabetic patients to assess if AMPK could link diabetes and the higher incidence of atherosclerosis in these patients.