title: Constitutive smooth muscle tumour necrosis factor regulates microvascular myogenic responsiveness and systemic blood pressure.
abstract: Tumour necrosis factor (TNF) is a ubiquitously expressed cytokine with functions beyond the immune system. In several diseases, the induction of TNF expression in resistance artery smooth muscle cells enhances microvascular myogenic vasoconstriction and perturbs blood flow. This pathological role prompted our hypothesis that constitutively expressed TNF regulates myogenic signalling and systemic haemodynamics under non-pathological settings. Here we show that acutely deleting the TNF gene in smooth muscle cells or pharmacologically scavenging TNF with etanercept (ETN) reduces blood pressure and resistance artery myogenic responsiveness; the latter effect is conserved across five species, including humans. Changes in transmural pressure are transduced into intracellular signals by membrane-bound TNF (mTNF) that connect to a canonical myogenic signalling pathway. Our data positions mTNF 'reverse signalling' as an integral element of a microvascular mechanosensor; pathologic or therapeutic perturbations of TNF signalling, therefore, necessarily affect microvascular tone and systemic haemodynamics.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8.|Toronto Centre for Microvascular Medicine at TBEP, University of Toronto, 661 University Avenue, 14th floor, Toronto, Ontario, Canada M5G 1M1.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kroetsch
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8.|Toronto Centre for Microvascular Medicine at TBEP, University of Toronto, 661 University Avenue, 14th floor, Toronto, Ontario, Canada M5G 1M1.|Keenan Research Centre at St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levy
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Hangjun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, University Health Network, R. Fraser Elliott Building, 1st Floor, 190 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Roozbeh
authors.initials: R
authors.lastname: Aschar-Sobbi
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8.|Toronto Centre for Microvascular Medicine at TBEP, University of Toronto, 661 University Avenue, 14th floor, Toronto, Ontario, Canada M5G 1M1.
authors.forename: Darcy
authors.initials: D
authors.lastname: Lidington
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.|Centre for Molecular Medicine, University of Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Engelhardt Institute of Molecular Biology and Lemonosov Moscow State University, 32 Vavilov Street, Moscow 119991, Russia.|German Rheumatism Research Center, a Leibniz Institute, Chariteplatz 1, Berlin 10117, Germany.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: Division of Cardiology, University Health Network, R. Fraser Elliott Building, 1st Floor, 190 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.|Heart &Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, C. David Naylor Building, 6 Queens Park Cresc. West, Toronto, Ontario, Canada M5S 3H2.|Department of Biology, York University, Farquharson Building, 110 Campus Walk, Toronto, Ontario, Canada M3J 2S5.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8.|Heart &Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, C. David Naylor Building, 6 Queens Park Cresc. West, Toronto, Ontario, Canada M5S 3H2.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Heximer
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8.|Toronto Centre for Microvascular Medicine at TBEP, University of Toronto, 661 University Avenue, 14th floor, Toronto, Ontario, Canada M5G 1M1.|Keenan Research Centre at St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8.|Heart &Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, C. David Naylor Building, 6 Queens Park Cresc. West, Toronto, Ontario, Canada M5S 3H2.
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D004285:Dogs; D000068800:Etanercept / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000517:prevention & control; D006801:Humans; D008297:Male; D008647:Mesocricetus; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D018482:Muscle, Skeletal / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013045:Species Specificity; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D014661:Vasoconstriction
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept