Molecular Mechanisms of Cerebral Vascular Autoregulation

脑血管自动调节的分子机制

• 批准号: 124911428
• 负责人: Professor Dr. Maik Gollasch
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin D - Geriatrie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/124911428?language=en
• 关键词: Molecular; Mechanisms; Cerebral; Vascular; Autoregulation

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.

血压是人类中风最一致、最有效的预测指标。小的大脑动脉维持肌源性张力，以应对血压变化，并维持大脑中的血流恒定。血管壁拉伸是主要的刺激因素；然而，其分子机制仍然难以捉摸。尽管已有研究表明GQ蛋白偶联受体(GPCRs)可以引起一般的牵张反应，但目前还不清楚血管平滑肌中的哪种GPRC发挥这一特定功能。这项研究将确定大脑循环中动脉平滑肌机械感知的分子机制。本研究旨在确定体内脑动脉的机械感觉机制，该机制涉及AT1a受体与特定的G蛋白(GQ/11)偶联，作为完成肌源性反应的必要信号通路。我们将遵循这样的假设，即动脉机械激活发生在没有血管紧张素原和存在药理学AT1受体阻断的情况下。它将确定潜在的离子机制，重点是KCNQ钾通道和TMEM16A氯通道，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AT1a受体信号传递的范围，我们将研究选择性拮抗G蛋白激活和信号传递的偏向AT1受体配体。目前的研究有望发现GPCR功能的基本分子机制，以及调节脑血流的Bayliss效应的潜在机制。