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

内皮素系统和肌原性张力：中枢神经系统阻力动脉中 G 蛋白偶联受体信号传导

• 批准号: RGPIN-2014-05162
• 负责人: Kelly, Melanie
• 金额: $ 2.55万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629235
• 关键词: ENDOTHELIN; SYSTEM; MYOGENIC; TONE; PROTEIN

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.

血压是当心脏将血液泵送到全身时（灌注）施加在动脉壁上的力。由于许多因素，包括身体姿势和活动的变化，血压在一天中会发生变化，这可能会改变血液输送到我们体内器官的情况。某些器官，包括大脑和眼睛，对灌注压的变化非常敏感，并且具有使它们能够保持恒定血流的内置机制（自动调节）。其中一种有助于自我调节的机制称为肌源性张力。这是血管壁中的肌细胞的性质，其通过收缩（血管收缩）来抵消血管中增加的灌注压以维持恒定的血流。产生肌源性张力的机制还不清楚，但涉及肌肉细胞中的蛋白质，这些蛋白质充当微小的应变计（“机械传感器”），以发出血管扩张（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，也不知道它们在灌注压增加时如何向血管发出收缩信号。该研究项目正在研究大脑和眼睛血管系统中肌源性张力信号的机制。具体来说，我们感兴趣的是确定肌肉细胞中的专门信号蛋白，称为内皮素受体，如何响应血管壁的拉伸。内皮素受体在血流调节中非常重要，新的证据表明它们受血管壁应变的影响，并可作为机械传感器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敏感的生物测定来检测和测量内皮素受体信号在孤立的血管和平滑肌细胞的大脑和眼睛的细胞壁被拉伸时的变化。这些信息将提供关于血管中的物理力如何转换为生化和电信号的新知识。适当的灌注在体内脆弱的器官是必不可少的生命，这项研究将提供一个更好地了解这些重要的稳态机制。