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

血压是心脏将血液输送到全身(灌流)时施加在动脉壁上的力。血压在一天中由于许多因素的变化而变化，包括身体位置和活动的变化，这可以改变血液输送到我们身体各器官的方式。某些器官，包括大脑和眼睛，对灌流压力的变化非常敏感，并具有内置的机制，使它们能够保持恒定的血流量(自动调节)。促进自身调节的机制之一被称为肌源性张力。这是血管壁中的肌肉细胞的一种特性，它通过收缩(血管收缩)来维持恒定的血液流动，从而抵消血管中增加的灌流压力。产生肌张力的机制还不是很清楚，但涉及到肌肉细胞中的蛋白质，这些蛋白质充当微小的应力计(“机械传感器”)，发出血管扩张(拉伸)的信号。尽管这些机械传感器很重要，但我们不知道它们的身份，以及当灌流压力增加时，它们是如何向血管发出收缩信号的。这项研究计划正在研究大脑和眼睛血管系统中发出肌源性张力信号的机制。具体地说，我们感兴趣的是确定肌肉细胞中被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非常重要的作用，新的证据表明，它们受到血管壁张力的影响，可以作为机械传感器来触发和放大血管收缩。我们的研究计划将使用最先进的显微成像技术和灵敏的生物检测方法来检测和测量当细胞壁拉伸时，大脑和眼睛的分离血管和平滑肌细胞中内皮素受体信号的变化。这些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。体内脆弱器官的适当灌流对生命至关重要，这项研究将提供对这些重要的动态平衡机制的更好理解。

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.