Oxidative stress and endothelial function
The vascular endothelium is critical for the maintenance of cardiovascular homeostasis, where it maintains an antithrombotic, anti-inflammatory and antiatherogenic state within the artery wall. In disease, the endothelium fails in its ability to regulate this equilibrium and results in endothelial dysfunction – a clinically relevant process occurring during atherosclerosis, diabetes and chronic kidney diseases. Vascular oxidative stress is a primary cause of endothelial dysfunction, of which the mechanisms and stimuli involved are not fully characterised. Identifying novel reparatory mechanism(s) and reducing oxidative stress is fundamental in re-establishing endothelium integrity. This project aims to examine how oxidative stress dysregulates endothelial cell function, and how specific molecules such as TNF ligands can act as antioxidants, improve cell homeostasis and function in disease.
Generation of new blood vessels
Diabetics are three to four times more likely to develop atherosclerotic coronary and peripheral artery disease (PAD), conditions where narrowed arteries reduce blood flow to the heart and limbs. This is a major risk factor for lower-limb amputation and increased risk of myocardial infarction. Current interventions are insufficient in many patients because extensive disease precludes effective revascularisation. One option is to stimulate blood vessel growth in order to restore blood flow, preserve tissue survival and maintain optimal organ function. Our publication showing TRAIL (TNF-related apoptosis-inducing ligand) stimulates angiogenesis and vessel stability/remodelling in PAD highlights an exciting and novel therapeutic possibility for patients in which current treatments have no benefit. The broad aim of this project is to identify whether TRAIL signals can stimulate blood vessel development in diabetes, in the limb, and in the heart during ischaemia. This work will lay the foundations for future intervention studies utilising TRAIL signals as novel therapeutics in stimulating blood vessel growth in diabetics with PAD and myocardial infarction.