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

血压是心脏向全身泵血（灌注）时施加在动脉壁上的力。血压全天都在变化，这是许多因素的结果，包括身体姿势和活动的变化，这可能会改变血液向身体器官的输送。某些器官，包括大脑和眼睛，对灌注压的变化非常敏感，并且具有内在的机制，使它们能够保持恒定的血流量（自动调节）。其中一种促进自我调节的机制被称为肌原性张力。这是血管壁肌肉细胞的一种特性，它通过收缩（血管收缩）来抵消血管中增加的灌注压力，以维持恒定的血液流动。产生肌张力的机制尚不清楚，但涉及肌肉细胞中的蛋白质，这些蛋白质作为微小应变计（“机械传感器”）来指示血管扩张（拉伸）。尽管这些机械传感器很重要，但我们不知道它们的身份，也不知道它们是如何在灌注压力增加时发出血管收缩的信号的。这个研究项目正在研究大脑和眼睛血管系统中肌张力信号的机制。具体来说，我们感兴趣的是确定肌肉细胞中称为内皮素受体的特殊信号蛋白如何对血管壁的拉伸做出反应。内皮素受体在血流调节中起着重要作用，新的证据表明它们受血管壁张力的影响，可以作为机械传感器触发和放大血管收缩。我们的研究项目将使用最先进的显微成像技术和灵敏的生物测定来检测和测量当细胞壁被拉伸时，孤立血管和大脑和眼睛平滑肌细胞中内皮素受体信号的变化。这一信息将为血管中的物理力量如何转化为生化和电信号提供新的知识。机体脆弱器官的适当灌注对生命至关重要，本研究将有助于更好地理解这些重要的体内平衡机制。

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.