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.
Cui
Xu
X
Department of Neurology, Henry Ford Health System, Detroit, Michigan 48202, USA.
Chen
Jieli
J
Zacharek
Alex
A
Roberts
Cynthia
C
Yang
Yuping
Y
Chopp
Michael
M
D053687:Adult Stem Cells / Q000187:drug effects*; D000704:Analysis of Variance; D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D002552:Cerebral Ventricles / Q000473:pathology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D009603:Nitroso Compounds / Q000008:administration & dosage*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D042683:Angiopoietin-1; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D019718:Receptors, CXCR4; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D042787:Receptor, TIE-2