The role of endothelial tryptophan hydroxylase in pulmonary vascular remodelling: an integrated approach

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Serotonin is a chemical that can act on the blood vessels of the lungs to cause them to thicken. This can lead to high blood pressure in the lungs. The enzyme responsible for the synthesis of serotonin that affects the lungs is tryptophan hydroxlase 1. Blood vessels have three layers, an outer layer of adventitial cells, a muscular layer and an inner layer of cells called endothelial cells. We will determine if tryptophan hydroxlase 1 causes synthesis of serotonin by the endothelial cells and if this serotonin can then act on the adjacent muscle and adventitial cells to make them grow and cause thickening of the artery. We will also determine if hypoxia (a reduction in oxygen) can stimulate an increase in endothelial cell serotonin synthesis and release and that this contributes to hypoxia-induced thickening of the blood vessels. We will use genetically modified mice which lack tryptophan hydroxlase 1 in our studies as well as isolated smooth muscle, adventitial and endothelial cells. We will also examine the feasilbility of knocking out tryptophan hydroxlase 1 in the endothelial cells in the whole animal using novel gene transfer techniques.