Kenji Yagi1, Darcy Lidington1, Hoyee Wan1, Jessica C Fares1, Anja Meissner1, Manabu Sumiyoshi1, Jinglu Ai1, Warren D Foltz1, Sergei A Nedospasov1, Stefan Offermanns1, Shinji Nagahiro1, R Loch Macdonald1, Steffen-Sebastian Bolz2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: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: Forrest A Brooks; Uvieoghene Ughwanogho; Galen V Henderson; Randie Black-Schaffer; Farzaneh A Sorond; Can Ozan Tan Journal: Am J Phys Med Rehabil Date: 2018-05 Impact factor: 2.159
Authors: Marcel A Kamp; Jasper H van Lieshout; Maxine Dibué-Adjei; Jasmin K Weber; Toni Schneider; Tanja Restin; Igor Fischer; Hans-Jakob Steiger Journal: Transl Stroke Res Date: 2017-01-30 Impact factor: 6.829
Authors: Christian Burrell; Nicole E Avalon; Jason Siegel; Michael Pizzi; Tumpa Dutta; M Cristine Charlesworth; William D Freeman Journal: Expert Rev Neurother Date: 2016-07-11 Impact factor: 4.618