Nitric oxide donor up-regulation of SDF1/CXCR4 and Ang1/Tie2 promotes neuroblast cell migration after stroke.

We tested the hypothesis that a nitric oxide donor, DETA-NONOate, up-regulates stromal cell-derived factor-1 (SDF1) and angiopoietin 1 (Ang1) in the ischemic brain and their respective receptors chemokine CXC motif receptor 4 (CXCR4) and Tie2 in the subventricular zone (SVZ) and thereby promote SVZ neuroblast cell migration after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo), and 24 hr later DETA-NONOate (0.4 mg/kg) or phosphate-buffered solution was intravenously administered. Mice were sacrificed at 14 days for histological assessment or sacrificed at 3 days for analysis by real-time polymerase chain reaction and migration after MCAo. To elucidate whether SDF1/CXCR4 and Ang1/Tie2 pathways mediate DETA-NONOate-induced SVZ migration after stroke, SDF1alpha, Ang1 peptide, a specific antagonist of CXCR4 (AMD3100), and a neutralizing antibody of Tie2 (anti-Tie2) were used in vitro. DETA-NONOate significantly increased the percentage area of doublecortin (DCX, a marker of migrating neuroblasts)-immunoreactive cells in the SVZ and ischemic boundary zone. DETA-NONOate significantly increased the expression of SDF1 and Ang1 in the ischemic border and up-regulated CXCR4 and Tie2 in the SVZ compared with MCAo control. DCX-positive cell migration from SVZ explants was significantly increased in the DETA-NONOate treatment group compared with MCAo-alone animals. In vitro, SDF1alpha and Ang1 significantly increased SVZ explants cell migration. In addition, inhibition of CXCR4 or Tie2 significantly attenuated DETA-NONOate-induced SVZ cell migration. Our data indicate that treatment of stroke with a nitric oxide donor up-regulates SDF1/CXCR4 and Ang1/Tie2 pathways and thereby likely increases SVZ neuroblast cell migration.
AuthorsXu Cui, Jieli Chen, Alex Zacharek, Cynthia Roberts, Yuping Yang, Michael Chopp
JournalJournal of neuroscience research (J Neurosci Res) Vol. 87 Issue 1 Pg. 86-95 (Jan 2009) ISSN: 1097-4547 [Electronic] United States
PMID18711749 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright2008 Wiley-Liss, Inc.
Chemical References
  • Angiopoietin-1
  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Nitric Oxide Donors
  • Nitroso Compounds
  • Receptors, CXCR4
  • 2,2'-(hydroxynitrosohydrazono)bis-ethanamine
  • Receptor, TIE-2
  • Adult Stem Cells (drug effects)
  • Analysis of Variance
  • Angiopoietin-1 (metabolism)
  • Animals
  • Cell Movement (drug effects)
  • Cerebral Ventricles (pathology)
  • Chemokine CXCL12 (genetics, metabolism)
  • Disease Models, Animal
  • In Vitro Techniques
  • Infarction, Middle Cerebral Artery (drug therapy, pathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Donors (administration & dosage)
  • Nitroso Compounds (administration & dosage)
  • Receptor, TIE-2 (metabolism)
  • Receptors, CXCR4 (metabolism)
  • Up-Regulation (drug effects)

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