title: Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes.
abstract: Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to the microcirculation. We demonstrate that skeletal muscle resistance arteries isolated from patients with diabetes have augmented myogenic tone, despite reasonable blood glucose control. To understand the mechanisms, we titrated a standard diabetes mouse model (high-fat diet plus streptozotocin [HFD/STZ]) to induce a mild increase in blood glucose levels. HFD/STZ treatment induced a progressive myogenic tone augmentation in mesenteric and olfactory cerebral arteries; neither HFD nor STZ alone had an effect on blood glucose or resistance artery myogenic tone. Using gene deletion models that eliminate tumor necrosis factor (TNF) or sphingosine kinase 1, we demonstrate that vascular smooth muscle cell TNF drives the elevation of myogenic tone via enhanced sphingosine-1-phosphate (S1P) signaling. Therapeutically antagonizing TNF (etanercept) or S1P (JTE013) signaling corrects this defect. Our investigation concludes that vascular smooth muscle cell TNF augments resistance artery myogenic vasoconstriction in a diabetes model that induces a small elevation of blood glucose. Our data demonstrate that microvascular reactivity is an early disease marker and advocate establishing therapies that strategically target the microcirculation.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Meghan
authors.initials: M
authors.lastname: Sauvé
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Sonya K
authors.initials: SK
authors.lastname: Hui
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Danny D
authors.initials: DD
authors.lastname: Dinh
authors.affiliation: Spatio-Temporal Targeting and Amplification of Radiation Response Innovation Centre, Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Foltz
authors.affiliation: Division of Cell and Molecular Biology, Toronto General Hospital Research Institute, Toronto, Ontario, Canada.
authors.forename: Abdul
authors.initials: A
authors.lastname: Momen
authors.affiliation: Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada Division of Cell and Molecular Biology, Toronto General Hospital Research Institute, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kroetsch
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Darcy
authors.initials: D
authors.lastname: Lidington
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada sts.bolz@utoronto.ca.
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D000068800:Etanercept / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009213:Myography; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; C471998:JTE 013; D008246:Lysophospholipids; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; D013110:Sphingosine; D000068800:Etanercept