Molecular Mechanisms of Cerebral Vascular Autoregulation

血压是人类中风最一致和最有力的预测因素。小脑动脉维持肌源性张力以响应血压变化并维持脑中的血流恒定。血管壁拉伸是主要的刺激，然而，分子机制仍然是难以捉摸的。虽然已经表明，Gq蛋白偶联受体（GPCRs）可以引起一般的牵张反应，目前还不清楚，在血管平滑肌中的GPRs发挥这一特定的功能。该研究将确定脑循环中动脉平滑肌机械传感的分子机制。该研究旨在确定体内脑动脉中的机械感应机制，该机制涉及与特定G蛋白（Gq/11）偶联的AT 1a受体作为完成肌源性反应的重要信号通路。我们将遵循这样的假设，即动脉机械激活发生在血管紧张素原的情况下，并在药物AT 1受体阻滞剂的存在下。它将确定潜在的离子机制，重点是KCNQ钾和TMEM 16 a氯离子通道，已知在这些动脉中表达。在本研究中，将使用基因修饰的小鼠模型。为了确定G蛋白非依赖性AT 1A受体信号传导的范围，我们将研究选择性拮抗G蛋白活化和信号传导的偏性AT 1受体配体。目前的研究有望发现GPCR功能的基本分子机制和调节脑血流的Bayliss效应的机制。

Blood pressure is the most consistent and powerful predictor of stroke in humans. Small cerebral arteries maintain myogenic tone to respond to blood pressure variations and to maintain blood flow constant in the brain. Vascular wall stretch is the major stimulus; however, the molecular mechanisms are still elusive. Although it has been suggested that Gq protein-coupled receptors (GPCRs) can elicit a general stretch response, it is unclear which GPRC in vascular smooth muscle exerts this specific function. The study will identify molecular mechanisms for mechano-sensing in arterial smooth muscle in the cerebral circulation. The study aims to identify a mechano-sensing mechanism in cerebral arteries in vivo that implicate the AT1a receptor coupled to a specific G-protein (Gq/11) as an essential signaling pathway to accomplish the myogenic response. We will follow the hypothesis that arterial mechano-activation occurs in the absence of angiotensinogen and in the presence of pharmacological AT1 receptor blockade. It will determine underlying ionic mechanisms with focus on KCNQ potassium and TMEM16a chloride channels, known to be expressed in these arteries. In the present study, gene-modified mouse models will be used. To determine the scope of G-protein-independent AT1A receptor signaling, we will study biased AT1 receptor ligands that selectively antagonize G protein activation and signaling. The present studies are expected to discover fundamental molecular mechanisms of GPCR function and mechanisms underlying the Bayliss effect of regulated brain blood flow.