Molecular Mechanisms of Cerebral Vascular Autoregulation

• Applicant: Professor Dr. Maik Gollasch
• Subject Area: Nephrology
• Term: from 2009 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 124911428

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.

• DFG Programme: Research Grants