THE ENDOTHELIN SYSTEM AND MYOGENIC TONE: G PROTEIN COUPLED RECEPTOR SIGNALING IN RESISTANCE ARTERIES OF THE CENTRAL NERVOUS SYSTEM

Blood pressure is the force exerted on arterial walls as the heart pumps blood throughout the body (perfusion). Blood pressure changes throughout the day as a result of many factors including variation in body position and activity and this can change the delivery of blood to organs in our body. Certain organs, including the brain and the eye, are very sensitive to changes in perfusion pressure, and have built-in mechanisms that enable them to maintain constant blood flow (autoregulation). One of the mechanisms that contributes to autoregulation is called myogenic tone. This is a property of muscle cells in the blood vessel wall, which counteract increased perfusion pressure in the vessel by contracting (vasoconstriction) to maintain constant blood flow. The mechanisms that generate myogenic tone are not well understood but involve proteins in the muscle cells that act as minute strain gauges ("mechanosensors") to signal blood vessel distention (stretch). Despite the importance of these mechanosensors, we don't know their identities and exactly how they signal the blood vessel to constrict when the perfusion pressure increases. This research program is studying the mechanisms that signal myogenic tone in the vasculature of the brain and the eye. Specifically, we are interested in determining how specialized signaling proteins in muscle cells, called endothelin receptors, respond to stretch of the vessel wall. Endothelin receptors are very important in blood flow regulation and new evidence indicates that they are affected by blood vessel wall strain and could act as mechanosensors to trigger and amplify vasoconstriction. Our research program will use state-of the art microscopic imaging techniques and sensitive bioassays to detect and measure alterations in endothelin receptor signaling in isolated blood vessels and smooth muscle cells of the brain and the eye when the cell wall is stretched. This information will provide new knowledge on the how physical forces in blood vessels are transduced to biochemical and electrical signals. Appropriate perfusion of vulnerable organs in the body is essential for life and this research will provide a better understanding of these important homeostatic mechanisms.