title: Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat.
abstract: BACKGROUND
  Cerebral ischemia is usually characterized by a reduction in local blood flow and metabolism and by disruption of the blood-brain barrier in the infarct region. The formation of oedema and opening of the blood-brain barrier in stroke is associated with enhanced expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1).
  
  
  RESULTS
  Here, we found an infarct volume of 24.8 +/- 2% and a reduced neurological function after two hours of middle cerebral artery occlusion (MCAO), followed by 48 hours of recirculation in rat. Immunocytochemistry and confocal microscopy revealed enhanced expression of MMP-9, TIMP-1, and phosphorylated ERK1/2 in the smooth muscle cells of the ischemic MCA and associated intracerebral microvessels. The specific MEK1/2 inhibitor U0126, given intraperitoneal zero or 6 hours after the ischemic event, reduced the infarct volume significantly (11.8 +/- 2% and 14.6 +/- 3%, respectively; P < 0.05), improved neurological function, normalized expression of phosphorylated ERK1/2, and reduced expression of MMP-9 and TIMP-1 in the vessel walls. Administration of U0126 12 hours after MCAO did not alter the expression of MMP-9. Immunocytochemistry showed no overlap in expression between MMP-9/TIMP-1 and the astrocyte/glial cell marker GFAP in the vessel walls.
  
  
  CONCLUSIONS
  These data are the first to show that the elevated vascular expression of MMP-9 and TIMP-1, associated with breakdown of the blood-brain barrier following focal ischemia, are transcriptionally regulated via the MEK/ERK pathway.
authors.affiliation: Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. aida.maddahi@med.lu.se
authors.forename: Aida
authors.initials: A
authors.lastname: Maddahi
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Chen
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism; D009460:Neurologic Examination; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013778:Tetrazolium Salts; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D002070:Butadienes; D005904:Glial Fibrillary Acidic Protein; D009570:Nitriles; D013778:Tetrazolium Salts; D019715:Tissue Inhibitor of Metalloproteinase-1; C113580:U 0126; C009591:triphenyltetrazolium; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1