title: Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage.
abstract: OBJECTIVE
  Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAH: it links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling.
  
  
  METHODS
  Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used.
  
  
  RESULTS
  We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH.
  
  
  CONCLUSIONS
  Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti-sphingosine-1-phosphate treatment may significantly improve clinical outcome.
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Yagi
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Darcy
authors.initials: D
authors.lastname: Lidington
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Hoyee
authors.initials: H
authors.lastname: Wan
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Fares
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Anja
authors.initials: A
authors.lastname: Meissner
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Manabu
authors.initials: M
authors.lastname: Sumiyoshi
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Jinglu
authors.initials: J
authors.lastname: Ai
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Warren D
authors.initials: WD
authors.lastname: Foltz
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
authors.affiliation: From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.). sts.bolz@utoronto.ca.
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology; D018390:Gene Targeting / Q000379:methods; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D010656:Phenylephrine / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000172:deficiency; D013345:Subarachnoid Hemorrhage / Q000378:metabolism* / Q000503:physiopathology* / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000172:deficiency; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014666:Vasomotor System / Q000187:drug effects / Q000502:physiology
chemical_list: D008246:Lysophospholipids; D014409:Tumor Necrosis Factor-alpha; D010656:Phenylephrine; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: inflammation; muscle, smooth, vascular; signal transduction; sphingosine kinase-1