title: Mechanosensitive Gq/11Protein-Coupled Receptors Mediate Myogenic Vasoconstriction.
abstract: Myogenic vasoconstriction (Bayliss effect) is mediated by vascular smooth muscle cells (VSMCs) of small resistance arteries sensing mechanical forces. During the last three decades, several proteins have been proposed as VSMC mechanosensors. Our previous studies highlighted agonist-independent mechanical activation of Gq/11protein-coupled receptors (Gq/11PCRs) in VSMCs of resistance arteries. In particular, angiotensin II AT1 receptors (AT1Rs) emerged as mechanosensors mediating myogenic tone. Moreover, we found that the AT1Breceptor isoform was more mechanosensitive than the AT1Areceptor. Interestingly, cysteinyl leukotriene 1 receptors (CysLT1Rs) were up-regulated in AT1R-deficient arteries as an essential backup strategy to compensate for the loss of vasoconstrictor receptors. Up-regulation of CysLT1Rs resulted in increased myogenic tone at low intraluminal pressures resulting in hyperactivity of AT1R-deficient arteries. Only at high intraluminal pressures myogenic tone was reduced, thus reflecting the loss of AT1Rs. Further, CysLT1Rs were involved in myogenic vasoconstriction of wild-type arteries. Simultaneous blockade of AT1Rs and CysLT1Rs in wild-type arteries caused reduction in myogenic tone of more than 60% comparable to the application of the selective Gq/11-protein inhibitor YM-254890. Our findings suggest that AT1Rs and CysLT1Rs are crucial mechanosensors in resistance arteries mediating 60% of myogenic vasoconstriction via the Gq/11-protein pathway without involvement of endogenous agonists.
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilians University of Munich, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Mederos Y Schnitzler
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilians University of Munich, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Storch
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilians University of Munich, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.|Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D006801:Humans; D008465:Mechanoreceptors; D040542:Mechanotransduction, Cellular; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D018077:Receptors, Leukotriene / Q000502:physiology*; D014661:Vasoconstriction
chemical_list: D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D018077:Receptors, Leukotriene; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C083169:leukotriene D4 receptor
keywords: GPCRs; mechanosensation; myogenic vasoconstriction