Keith Channon

Endothelial cell signalling and vascular disease     We aim to understand how early changes in the endothelium and the vascular wall are related to the initiation and development of vascular diseases, with a particular focus on nitric o xide signalling.    Diabetes, high cholesterol, smoking and high blood pressure are all associated with abnormalities in the function of the endothelium, the single-cell lining of blood vessels. Of particular significance are abnormalities in the action of nitric oxide (NO), one of several important molecules produced in the endothelium that help to maintain the health of the blood vessel wall. These abnormalities accelerate the processes that lead to vascular disease, including inflammation, thrombosis and atherosclerotic plaque formation. Production of NO, by nitric oxide synthase enzymes, is highly regulated and depends on the co-factor tetrahydrobiopterin, which is made within endothelial cells.  Once NO is produced, it interacts with molecular targets in the cell, but is rapidly inactivated by reactive oxygen species (ROS).  Nitric oxide synthases can produce ROS as well as NO, the balance between the two determining the biological actions and pathological importance of these pathways. In previous work, we have used both clinical studies and experimental models to explore the role of endothelial nitric oxide synthase and its regulation by tetrahydrobiopterin in vascular disease, in particular the inflammation associated with atherosclerotic plaque formation. We have developed transgenic models to increase tetrahydrobiopterin levels in the endothelium and other cell types, by overexpression of GTP cyclohydrolase 1 (GTPCH), the rate-limiting enzyme in its synthesis. We have also generated targeted knockouts of GTPCH, to work out how tetrahydrobiopterin is involved in normal function in the cardiovascular system elsewhere. In studies of patients with diabetes and coronary artery disease, we have examined changes in endothelial function, and nitric oxide and tetrahydrobiopterin levels, and how these relate to the clinical features of disease. We have carried out clinical trials of treatments to increase tetrahydrobiopterin levels and improve endothelial function.