title: Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway.
abstract: BACKGROUND
  MEK1/2 is a serine/threonine protein that phosphorylates extracellular signal-regulated kinase (ERK1/2). Cerebral ischemia results in enhanced expression of cerebrovascular contractile receptors in the middle cerebral artery (MCA) leading to the ischemic region. Here we explored the role of the MEK/ERK pathway in receptor expression following ischemic brain injury using the specific MEK1 inhibitor U0126.
  
  
  RESULTS
  Rats were subjected to a 2-h middle cerebral artery occlusion (MCAO) followed by reperfusion for 48-h and the ischemic area was calculated. The expression of phosphorylated ERK1/2 and Elk-1, and of endothelin ETA and ETB, angiotensin AT1, and 5-hydroxytryptamine 5-HT1B receptors were analyzed with immunohistochemistry using confocal microscopy in cerebral arteries, microvessels and in brain tissue. The expression of endothelin ETB receptor was analyzed by quantitative Western blot. We demonstrate that there is an increase in the number of contractile smooth muscle receptors in the MCA and in micro- vessels within the ischemic region. The enhanced expression occurs in the smooth muscle cells as verified by co-localization studies. This receptor upregulation is furthermore associated with enhanced expression of pERK1/2 and of transcription factor pElk-1 in the vascular smooth muscle cells. Blockade of transcription with the MEK1 inhibitor U0126, given at the onset of reperfusion or as late as 6 hours after the insult, reduced transcription (pERK1/2 and pElk-1), the enhanced vascular receptor expression, and attenuated the cerebral infarct and improved neurology score.
  
  
  CONCLUSIONS
  Our results show that MCAO results in upregulation of cerebrovascular ETB, AT1 and 5-HT1B receptors. Blockade of this event with a MEK1 inhibitor as late as 6 h after the insult reduced the enhanced vascular receptor expression and the associated cerebral infarction.
authors.affiliation: Division of Experimental Vascular Research, BMC A13, Lund University, 221 84 Lund, Sweden. Aida.Maddahi@med.lu.se
authors.forename: Aida
authors.initials: A
authors.lastname: Maddahi
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002070:Butadienes / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D007274:Injections, Intraperitoneal; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications; D015398:Signal Transduction / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D002070:Butadienes; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D009570:Nitriles; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D044302:Receptor, Serotonin, 5-HT1B; D011956:Receptors, Cell Surface; C113580:U 0126; D050807:ets-Domain Protein Elk-1; D048052:Mitogen-Activated Protein Kinase 3; D048370:MAP Kinase Kinase 2
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