title: Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway.
abstract: BACKGROUND
  Cerebral ischemia results in a rapid increase in contractile cerebrovascular receptors, such as the 5-hydroxytryptamine type 1B (5-HT₁(B)), angiotensin II type 1 (AT₁), and endothelin type B (ET(B)) receptors, in the vessel walls within the ischemic region, which further impairs local blood flow and aggravates tissue damage. This receptor upregulation occurs via activation of the mitogen-activated protein kinase pathway. We therefore hypothesized an important role for B-Raf, the first signaling molecule in the pathway. To test our hypothesis, human cerebral arteries were incubated at 37°C for 48 h in the absence or presence of a B-Raf inhibitor: SB-386023 or SB-590885. Contractile properties were evaluated in a myograph and protein expression of the individual receptors and activated phosphorylated B-Raf (p-B-Raf) was evaluated immunohistochemically.
  
  
  RESULTS
  5-HT₁(B), AT₁, and ET(B) receptor-mediated contractions were significantly reduced by application of SB-590885, and to a smaller extent by SB-386023. A marked reduction in AT₁ receptor immunoreactivity was observed after treatment with SB-590885. Treatment with SB-590885 and SB-386023 diminished the culture-induced increase of p-B-Raf immunoreactivity.
  
  
  CONCLUSIONS
  B-Raf signaling has a key function in the altered expression of vascular contractile receptors observed after organ culture. Therefore, specific targeting of B-Raf might be a novel approach to reduce tissue damage after cerebral ischemia by preventing the previously observed upregulation of contractile receptors in smooth muscle cells.
authors.affiliation: Department of Clinical Sciences, Lund University, Sweden. hilda.ahnstedt@med.lu.se
authors.forename: Hilda
authors.initials: H
authors.lastname: Ahnstedt
authors.forename: Hans
authors.initials: H
authors.lastname: Säveland
authors.forename: Ola
authors.initials: O
authors.lastname: Nilsson
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000368:Aged; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009924:Organ Culture Techniques; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000096:biosynthesis*; D044302:Receptor, Serotonin, 5-HT1B / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: C544065:AGTR1 protein, human; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D044302:Receptor, Serotonin, 5-HT1B; C508204:SB-590885; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases