Interactions between mts 1 and serotonin in vascular remodelling

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Thickening of blood vessels (known as remodelling) occurs in many diseases associated with the cardiovascular system and is related to high blood pressure (hypertension). This can occur in the blood vessels that supply the lungs (pulmonary arteries), those that supply the heart and the brain as well as those that supply blood to the rest of the body (systemic arteries). Many factors contribute to the remodelling of arteries. Recent evidence suggests that a chemical in the body known as serotonin can interact with another chemical known as mts1 to cause pulmonary arterial remodelling. This has been shown in isolated cells but whether or not this occurs in the whole animal requires investigation. We have established techniques designed to investigate pulmonary and systemic arteries in transgenic mice, both in the whole animal, at the level of the very small arteries and at the cellular level. Application of these techniques to mice that have an artificial increase in the expression of the pore that allows serotonin to enter the cell (the serotonin transporter) and mts1 will enable us to investigate this potentially important mechanism for vascular remodelling. In addition, lack of oxygen (hypoxia) is an important mediator of pulmonary arterial remodelling and we have developed techniques for exposing mice and cells to a hypoxic environment. This will be applied to study the interaction between hypoxia, serotonin and mts1. The major aim of the work is to establish, in the whole animal, if there is an important interaction between mts1 and serotonin that causes a remodelling of the pulmonary arteries. This will be done by examining these interactions in mice over-expressing mts1 and mice over-expressing the serotonin transporter. These mice will also be cross-bred to develop mice that over-express both the serotonin transporter and mts1. Further experiments will be carried out on blood vessels derived from these 'models' and from cells grown up in culture from these blood vessels. This will give a clear picture of how intracellular interactions relate to whole body function. There are many benefits and applications of this work, including knowledge of how mts1, serotonin and hypoxia affect vascular function, how this changes in disease and how such changes could be prevented. It will suggest novel therapies for remodelling diseases such as hypertension.