Large Artery Research
Efficient delivery of blood from the heart to the peripheral circulation depends on the integrity of large conduit arteries. Alterations in the mechanical properties of large arteries due to changes in the extracellular matrix of the arterial wall, or reduction in lumen diameter due to atherosclerosis adversely affect the function of large arteries, leading to cardiovascular complications.
Researchers in the Vascular Biology group are investigating the mechanisms that underlie these pathological changes. The main areas of our research and the investigators involved are detailed below.
Vascular calcification, the formation of mineralised tissue, bone and cartilage in the walls of blood vessels, is a common complication of diabetes, chronic kidney disease and atherosclerosis.
Calcification results in increased arterial stiffness, which increases the incidence of hypertension, left ventricular hypertrophy and heart failure. In atherosclerosis, calcification can also increase the risk of plaque rupture, increasing clot formation and in turn the occurrence of emboli, stoke and myocardial infarction.
Vascular calcification is a complex process which involves the osteo/chondrogenic differentiation of vascular smooth muscle cells (VSMCs), loss of inhibitors and gain of promoters, apoptosis of VSMCs and production of matrix vesicles. The over-arching goal of our research is to identify novel therapeutic targets to prevent or reduce this devastating pathology.
(Image: Vascular smooth muscle cell mineralisation with mineral stained red)
Cell-matrix biology of the vascular progenitor cell niche
Multilineage progenitor cells (MPCs) are located in perivascular niches throughout the body. This cellular reservoir is essential for normal repair and regeneration of blood vessels and many other tissues. Their potential for cardiovascular therapy is clear, given their availability and ability to differentiate along smooth muscle and endothelial lineages without provoking a host immunological response when implanted.
However, the aberrant differentiation of these cells leads to complications such as vascular calcification. The underlying biology of these primitive cells is still poorly defined and a major obstacle to their exploitation in cell-based therapies. With collaborators in the Wellcome Trust Centre for Cell-Matrix Research in the Faculty of Life Sciences, we are currently defining how the cell-matrix interface controls the survival, proliferation, recruitment and differentiation of these cells.
(Image: Progenitor cells (labelled red) associated with the extracellular matrix labelled green).
Atherosclerotic plaque formation in large and medium sized arteries is the major cause of cardiovascular disease. Complications occur when the plaque encroaches on the lumen reducing blood flow, or when plaque rupture occurs resulting in unstable angina, myocardial infarction, stroke and sudden death. Understanding the mechanisms that underlie the initiation, development and progression of plaque is a major goal in the treatment of cardiovascular disease.
Atherosclerotic lesions are characterised by inflammation, lipid and macrophage accumulation, cell death and fibrosis. Our studies are based around understanding the pathogenesis of atherosclerosis as well as investigations of myocardial regeneration following injury utilising experimental and translational models of atherosclerosis, heart failure and myocardial infarction.
(Image: Atherosclerotic plaque in a large artery).
Therapeutic Vascular Gene Transfer
Therapeutic vascular gene transfer, frequently referred to as Vascular Gene Therapy, is the transfer of nucleic acids into the tissues of the cardiovascular system with the intention of eliciting the expression of a protein that will confer a therapeutic biological effect. Gene Therapy has been directed, with rather limited success, at a variety of targets within the cardiovascular system over the last decade. In the last couple of years, however, a small number of cardiovascular pathologies have been shown to be amenable to clinically-useful therapeutic modulation by means of gene transfer.
Historically, the Vascular Gene Therapy group has investigated the utility of antifibrotic gene transfer in the prevention of accelerated atherosclerosis (in-stent restenosis and vein graft vasculopathy), and the optimization of non-viral gene transfer within vascular tissues. Our future objectives include the application of optimized non-viral gene transfer vectors to vascular and cardiac pathologies in the clinical setting, the application of antifibrotic gene transfer to vascular and cardiac pathology (and to fibrotic pathologies outwith the cardiovascular system), and therapeutic gene transfer into the cardiac conducting tissues as part of the biopacemaking group.
(Image: Expression of an antifibrotic transgene in a stented coronary artery (right) suppresses in-stent neointima formation and preserves vessel calibre by comparison with a control stented artery (left)).