Investigation of novel protein pathways which regulate vascular smooth muscle cell phenotype in neointimal hyperplasia

Cardiovascular disease remains the biggest killer in the developed world. In many cases, deaths from this disease result from a blockage of the arteries, typically in the heart. Surgical intervention of arteries is commonly used to prevent cardiovascular disease developing to a fatal degree, which consists of either balloon angioplasty (insertion of a small balloon into the artery to physically widen the blood vessel opening) or artery bypass (where another artery, commonly from the leg is inserted into the heart artery to bypass the blocked artery). Although these interventions have dramatically improved life expectancy in cardiovascular disease patients, in time the benefits are commonly lost as the blood flow in the arteries is blocked by a thickening blood vessel wall. Prevention of this blood vessel thickening, which occurs via an inappropriate growth of the cells in the artery wall, would dramatically improve the life expectancy of patients following surgical intervention. We now have evidence that a protein found within cells in the artery wall, and previously unknown, can regulate thickening of the artery observed following angioplasty and bypass surgery. This protein is called PEA-15 and our previous results have revealed that it prevents inappropriate growth of cells in the artery wall, i.e. it helps maintain healthy blood vessels. Our preliminary experiments indicate that PEA-15 is decreased in diseased arteries and this may lead to growth in cells from arteries and thickening of the blood vessel wall. In this study we will aim to fully understand the role of PEA-15 in blood vessels and its relation to cardiovascular disease. In addition, we propose that increasing PEA-15 may help prevent blood vessel thickening. In our study we will also focus on one agent which recent evidence suggests can increase PEA-15 in cells, vitamin D. Vitamin D has long been recognised as producing benefits in cardiovascular disease however how this occurs is not clear. Our experiments aim to demonstrate that vitamin D, by increasing PEA-15 in the cells of arteries, can be beneficial in preventing cardiovascular disease. This new information will provide further evidence of the potential therapeutic value of vitamin D in cardiovascular disease patients following angioplasty or bypass surgery.