Molecular Mechanisms of Cerebral Vascular Autoregulation

血压是人类中风最稳定、最有力的预测指标。脑小动脉维持肌原性张力以应对血压变化并维持脑内血流恒定。血管壁拉伸是主要刺激；然而，分子机制仍然是难以捉摸的。虽然有研究表明Gq蛋白偶联受体（gpcr）可以引起一般的拉伸反应，但尚不清楚血管平滑肌中的GPRC是哪一种发挥这种特定功能。本研究将确定脑循环中动脉平滑肌机械感应的分子机制。本研究旨在确定体内脑动脉中AT1a受体与特定g蛋白（Gq/11）偶联作为完成肌生成反应的重要信号通路的机械传感机制。我们将遵循动脉机械激活发生在缺乏血管紧张素原和存在药理AT1受体阻断的假设。它将确定潜在的离子机制，重点关注已知在这些动脉中表达的KCNQ钾和TMEM16a氯通道。在本研究中，将使用基因修饰的小鼠模型。为了确定不依赖G蛋白的AT1A受体信号传导的范围，我们将研究选择性拮抗G蛋白激活和信号传导的偏置AT1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.