Scheme: Wolfson Research Merit Awards
Organisation: University of Oxford
Dates: Apr 2010-Mar 2015
Summary: Arteries are the body’s active plumbing, diameter changes ensuring blood flow adequately supplies cell nutrients and helping to determine blood pressure, by controlling resistance across the vasculature. Changes in diameter reflect contraction and relaxation of very small ‘smooth’ muscle cells that wrap round to form the artery ‘tubes’. The muscle cells are influenced by a thin lining layer of endothelial cells in contact with the blood, and by nerves round the outside. Recent research, including our own, has found that normally endothelial cells continually decrease blood pressure by relaxing the smooth muscle through ‘hyperpolarization’. Hyperpolarization reflects the opening of small protein-lined pores in the membranes encasing endothelial cells, and transfers to the muscle by chemicals and physical connections (called gap-junctions). Cardiovascular disease compromises this influence, so the muscle contracts, increasing resistance and thus blood pressure to cause hypertension and other serious events, such as stroke and heart attack. The planned research will show how hyperpolarization in endothelial cells is integrated to regulate diameter up and down the length of arteries, thus controlling blood pressure and flow in our bodies, and potentially indicating new ways to treat high blood pressure and prevent stroke. My research over the last year has revealed important mechanisms underlying such spread that are of direct physiological relevance. We have found that the active form of NO released from the endothelium that is able to evoke hyperpolarization is HNO, or nitroxy. The hyperpolarization causes dilatation over distance. Also, physiologically active chemicals found in the circulation and involved in the stress responses, noradrenaline and adrenaline, also evoke hyperpolarization. Interestingly, at local sites in the artery wall other cellular mechanisms predominate to cause vasodilatation, but the hyperpolarization enables dilatation to spread upstream.