Extracellular matrix biology in health and disease
The extracellular matrix plays a key role in physiology and disease, illustrated by the role of fibrosis in disease and disorders due to mutations in extracellular matrix components. Mutations in collagen IV cause Mendelian forms of cerebrovascular disease, including cerebral small vessel disease and stroke, as well as eye and kidney defects, while common variants are a risk factor for haemorrhagic stroke in the general population. Cerebral small vessel disease is one of the leading causes of vascular dementia.
Counter-regulatory Renin Angiotensin System
In the body hormones travel via the bloodstream and engage receptors which contribute to the normal function of blood vessels, heart and kidney. One hormone, angiotensin II, can become overactive and contribute to cardiovascular disease, resulting in high blood pressure, enlargement of the heart and damage to kidneys. However, other members of this hormone family including angiotensin-(1-7) and angiotensin-(1-9) block the detrimental actions of angiotensin II, through mechanisms that are not well understood. Thus angiotensin-(1-7) and –(1-9) may be important therapeutic targets in cardiovascular disease and therefore it is important to fully understand how they function. We investigate the function of these potentially therapeutic peptides using a range of techniques. One of these is the use of gene transfer using viral vectors to express these molecules in different cells to study their function with the ultimate aim of developing new gene therapies. To achieve this we use different viral vectors which are able to efficiently deliver genes into different cell types in organs in the body.
Co-ordinated Regulation of Metabolism and Vascular Health
Co-ordinated Regulation of Metabolism and Vascular Health
Type 2 diabetes, a condition in which patients have reduced sensitivity to the hormone insulin, is closely linked with cardiovascular disease. My laboratory is interested in identifying the mechanisms that underlie this link between diabetes and cardiovascular disease. We have shown that insulin itself acts on the endothelial cells that line blood vessels to produce nitric oxide, a substance that relaxes blood vessels and prevents the clots that lead to heart attacks and strokes. In addition, we have demonstrated that a protein called “AMP-activated protein kinase (AMPK)” has similar beneficial effects on endothelial cells. We are currently investigating how insulin and AMPK regulate the cardiovascular system under conditions that mimic diabetes and cardiovascular disease. Our hope is that the results of our work will further expand our knowledge of how insulin and AMPK affect arteries, which will aid the development of future drugs and new therapies for the treatment of diabetes and cardiovascular disease.
Chronic inflammation of the arterial wall during atherosclerosis is now thought to be a key process contributing to plaque progression. The vessel wall is infiltrated by macrophages and T cells, which together with resident smooth muscle and endothelial cells produce cytokines, growth factors and other pro-inflammatory mediators in response to the presence of oxidized low-density lipoprotein (ox-LDL). Depending on their phenotype, T cells can either drive inflammation in plaques (Th1) or dampen inflammatory responses (Th2/Treg).
Interleukin (IL)-33 is a new member of the IL-1 family of cytokines that promotes Th2 type immune responses by signaling through the ST2L and IL-1RAcP dimeric receptor complex. Experimental studies in our lab demonstrate that exogenous administration of IL-33 in an ApoE-/- model reduced atherosclerotic lesions in the aortic sinus compared to vehicle control (Miller et al, 2008). Conversely, mice treated with intraperitoneal injections of sST2, the decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE-/- mice compared to control IgG-treated mice. Mechanistically, IL-33 markedly induced a switch from a pro-atherogenic Th1 to a protective Th2 phenotype (Figure 1). Current projects are investigating endothelial release of IL-33 and study of the role of endogenous IL-33 within the vessel wall.
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. I also have an interest in the activity of perivascular adipose tissue which surrounds blood vessels and how it can modulate vascular function in health and disease.
Role of Mitochondrial Dysfunction in Atherosclerosis
My research attempts to investigate the important molecular determinants underlying the cardiovascular pathology of atherosclerosis. Our previous work has identified the significance of the DNA damage response in vascular smooth muscle cells as being particularly important for cell and plaque fate. While developing a number of DNA damage prone transgenic models we identified intermediates of cell metabolism as disrupting mitochondrial energy homeostasis. Therefore, I’m particularly focused on the contribution of nuclear and mitochondrial DNA damage to the cellular energetics of the atherosclerotic plaque.
TGFbeta in Vascular Remodelling
Coronary heart disease is a leading cause of death in Scotland. Although lifestyle changes and prescription drugs can help treat coronary heart disease, revascularisation surgeries such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are sometimes necessary. The development of intimal hyperplasia after PCI or CABG significantly reduces their success rates, resulting in risky and costly repeat interventions. The cytokine transforming growth factor-beta (TGFß) promotes intimal hyperplasia and represents a promising target for gene therapy. However TGFß regulates many important cell and tissue processes, which means that a targeted and selective approach to modulate TGFß is essential. Additionally, recent studies have identified a novel TGFß signalling pathway that is activated during neointima formation in rodent coronary heart disease models. My work is focused on improving our understanding of how TGFß signalling regulates the development of intimal hyperplasia. We are also interested in generating gene therapy strategies targeting the TGFß pathway that could potentially be used to prevent the development of intimal hyperplasia after PCI or CABG, thereby ameliorating the outcome of these two revascularisation surgeries.
Vascular Biology of Hypertension
Hypertension, high blood pressure (BP), and its consequences contribute significantly to worldwide morbidity and mortality. Hypertension is the major cause of stroke, kidney disease and cardiac failure in Scotland, and it is predicted that by 2025 the number of adults with hypertension will increase by 60%. This is attributed, in part, to the growing problem of associated risk factors including obesity and diabetes. Despite its widespread prevalence and intense research into its pathophysiology and etiology, only 5% of patients with hypertension have an identifiable cause. Hypertension is the product of dynamic interactions between genetic, physiological and environmental factors. Most patients with high BP have “essential hypertension”, the cause of which remains unknown.
Diseases of the blood vessels and heart have the highest mortality rates in the world. In advanced disease, critical blood vessels can become blocked by a build-up of cells and lipids within the walls of the blood vessel. This can severely limit blood flow to affected organs such as the heart and is a major cause of high blood pressure, heart attacks and stroke. Treatments include surgery to restore blood flow by re-widening of the blood vessels by balloon catheter and permanent placement of a metal supports called ‘stents’ or by blood vessel bypass. These surgeries can alleviate symptoms but cause blood vessel damage that promotes surrounding cells to divide and blood vessel re-narrowing in a high number of patients. We have recently identified that proteins called connexins, found in all blood vessel cells, are directly linked to the regulation of cell division. My work focuses on identifying the impact of specific connexin proteins in blood vessel disease, defining how they interact with other proteins to promote cells to divide and ways in which we can disrupt the protein in disease. This could potentially lead to novel therapeutic targets for treatment of blood vessel diseases.