title: Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats.
abstract: Recombinant osteopontin (rOPN) has been reported to be neuroprotective in stroke animal models. The purpose of this study is to investigate a potential role and mechanism of nasal administration of rOPN on preserving the vascular smooth muscle phenotype in early brain injury after subarachnoid hemorrhage (SAH).
  
  
  
  One hundred and ninety-two male adult Sprague-Dawley rats were used. The SAH model was induced by endovascular perforation. Integrin-linked kinase small interfering RNA was intracerebroventricularly injected 48 hours before SAH. The integrin receptor antagonist fibronectin-derived peptide Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP), focal adhesion kinase inhibitor Fib-14, and Rac-1 inhibitor NSC23766 were administered 1 hour before SAH induction. rOPN was administered via the intracerebroventricular and nasal route after SAH. SAH grade, neurological scores, brain water content, brain swelling, hematoxylin and eosin staining, India ink angiography, Western blots, and immunofluorescence were used to study the mechanisms of rOPN on the vascular smooth muscle phenotypic transformation.
  
  
  
  The marker proteins of vascular smooth muscle phenotypic transformation α-smooth muscle actin decreased and embryonic smooth muscle myosin heavy chain (SMemb) increased significantly at 24 and 72 hours in the cerebral arteries after SAH. rOPN prevented the changes of α-smooth muscle actin and SMemb and significantly alleviated neurobehavioral dysfunction, increased the cross-sectional area and the lumen diameter of the cerebral arteries, reduced the brain water content and brain swelling, and improved the wall thickness of cerebral arteries. These effects of rOPN were abolished by GRGDSP, integrin-linked kinase small interfering RNA, and NSC23766. Intranasal application of rOPN at 3 hours after SAH also reduced neurological deficits.
  
  
  
  rOPN prevented the vascular smooth muscle phenotypic transformation and improved the neurological outcome, which was possibly mediated by the integrin receptor/integrin-linked kinase/Rac-1 pathway.
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: Budbazar
authors.initials: B
authors.lastname: Enkhjargal
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pearce
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hartman
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA.
authors.forename: Andre
authors.initials: A
authors.lastname: Obenaus
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA. johnzhang3910@yahoo.com nju_neurosurgery@163.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: From the Department of Neurosurgery (J.W., G.C.), the First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Physiology (J.W., Y.Z., P.Y., B.E., A.M., J.T., W.J.P., R.H., A.O., J.H.Z.), School of Behavioral Science (R.H.), Department of Pediatrics (A.O.), and Department of Anesthesiology (J.H.Z.), Loma Linda University, CA. johnzhang3910@yahoo.com nju_neurosurgery@163.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects*; D004195:Disease Models, Animal; D016023:Integrins / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D053495:Osteopontin / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy*; D020830:rac1 GTP-Binding Protein / Q000187:drug effects*; D000099200:Scaffold Protein ILK
chemical_list: D016023:Integrins; D018696:Neuroprotective Agents; D053495:Osteopontin; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D020830:rac1 GTP-Binding Protein; D000099200:Scaffold Protein ILK
keywords: blotting, Western; cerebral arteries; muscle; rats, Sprague-Dawley; smooth, vascular; subarachnoid hemorrhage