The vascular endothelium is critical for the maintenance of cardiovascular homeostasis, where it maintains an antithrombotic, anti-inflammatory and antiatherogenic state within the vessel wall. In disease, the endothelium fails in its ability to regulate this equilibrium and results in endothelial dysfunction.
One endothelium-dependent process dysregulated in cardiovascular disease (CVD) is angiogenesis, the development of new blood vessels from pre-existing vessels. This process involves the proliferation, migration and differentiation of endothelial cells to form microtubules, which are then stabilised by mural cells (such as pericytes and vascular smooth muscle cells). Angiogenesis is critical in normal physiological processes such as embryonic development, wound healing and tissue ischemia. It is also characteristic of many inflammatory diseases such as those seen in atherosclerosis and cancer. Understanding how angiogenesis is regulated under normal and pathologic conditions is critical for identifying new treatment options in disease.
Project
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.
This ongoing project seeks to identify novel molecules that stimulate stable blood vessel networks in atherosclerosis and diabetes-accelerated atherosclerosis in the limb during ischaemia. This work will lay the foundations for future intervention studies using TRAIL signals as novel therapeutics in stimulating blood vessel growth in diabetics with PAD and myocardial infarction. It will also identify new pathways and novel cell-cell interactions in angiogenesis.