title: Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels.
abstract: Activation of Ca2+-sensitive, large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) by local, ryanodine receptor-mediated Ca2+signals (Ca2+sparks) acts as a brake on pressure-induced (myogenic) vasoconstriction-a fundamental mechanism that regulates blood flow in small resistance arteries. We report that physiological intraluminal pressure within resistance arteries activated cGMP-dependent protein kinase (PKG) in VSMCs through oxidant-induced formation of an intermolecular disulfide bond between cysteine residues. Oxidant-activated PKG was required to trigger Ca2+sparks, BK channel activity, and vasodilation in response to pressure. VSMCs from arteries from mice expressing a form of PKG that could not be activated by oxidants showed reduced Ca2+spark frequency, and arterial preparations from these mice had decreased pressure-induced activation of BK channels. Thus, the absence of oxidative activation of PKG disabled the BK channel-mediated negative feedback regulation of vasoconstriction. Our results support the concept of a negative feedback control mechanism that regulates arterial diameter through mechanosensitive production of oxidants to activate PKG and enhance Ca2+sparks.
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, M13 9NT, UK.|King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London, SE1 7EH, UK.
authors.forename: Kaivan
authors.initials: K
authors.lastname: Khavandi
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, M13 9NT, UK.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Baylie
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, M13 9NT, UK.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Sugden
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, M13 9NT, UK.|Department of Pharmacology, University of Vermont, Vermont, 05405-0068, USA.
authors.forename: Majid
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, M13 9NT, UK.|Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen 4012, Hungary.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Csato
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London, SE1 7EH, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
authors.affiliation: Department of Pharmacology, University of Vermont, Vermont, 05405-0068, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Hill-Eubanks
authors.affiliation: Department of Pharmacology, University of Vermont, Vermont, 05405-0068, USA.
authors.forename: Adrian D
authors.initials: AD
authors.lastname: Bonev
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, M13 9NT, UK.|Department of Pharmacology, University of Vermont, Vermont, 05405-0068, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, M13 9NT, UK.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Greenstein
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D017869:Cyclic GMP-Dependent Protein Kinases