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Molecular Pharmacology

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Research ArticleArticle

Transforming Growth Factor-β1 Impairs Endothelin-1-Mediated Contraction of Brain Vessels by Inducing Mitogen-Activated Protein (MAP) Kinase Phosphatase-1 and Inhibiting p38 MAP Kinase

Xin-Kang Tong and Edith Hamel
Molecular Pharmacology December 2007, 72 (6) 1476-1483; DOI: https://doi.org/10.1124/mol.107.039602
Xin-Kang Tong
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Edith Hamel
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Abstract

Brain levels of transforming growth factor-β1 (TGF-β1) are increased in Alzheimer's disease and have been implicated in the associated cerebrovascular pathology. We recently reported that transgenic mice that overexpress TGF-β1 (TGF+ mice) display, with aging, selectively reduced endothelin-1 (ET-1)-mediated contractions. Because ET-1 is a key regulator of cerebrovascular tone and homeostasis, we investigated how increased levels of TGF-β1 could selectively alter this contractile response. We found that ETA receptors, via activation of p38 mitogen-activated protein (MAP) kinase, mediate the ET-1-induced contraction in mouse cerebral arteries, a response significantly decreased in aged TGF+ mice (-39%; p < 0.01) despite unaltered ETA receptor levels or affinity. In cerebrovascular smooth muscle cell cultures, long-term treatment with TGF-β1 significantly decreased (>50%; p < 0.05) the ET-1-induced activation of the p38 MAPK/27-kDa heat shock protein (HSP27) signaling pathway. This occurred with no effect upstream to p38 MAP kinase but with the concomitant induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) expression. Inhibition of MKP-1 expression with Ro-31-8220 or suppression of MKP-1 expression by short interfering RNA restored the ET-1-mediated p38 MAP kinase response. These results disclose a new role for long-term increases of TGF-β1in modulating cerebrovascular tone by dampening ET-1-mediated activation of the p38 MAPK/HSP27 signaling pathway. Such changes in ET-1-mediated signaling may help maintain vascular wall homeostasis by compensating for the diminished dilatory function induced by TGF-β1 and amyloid-β; brain levels of these two molecules are increased in patients with Alzheimer's disease.

Footnotes

  • This work was supported by grants MOP-64194 and MOP-5334 from the Canadian Institute of Health Research and by the Alzheimer's Society of Canada.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.039602.

  • ABBREVIATIONS: AD, Alzheimer's disease; Aβ, amyloid-β; TGF-β1, transforming growth factor-β1; ET-1, endothelin-1; ETA, endothelin receptor A; ETB, endothelin receptor B; MAP, mitogen-activated protein; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase or p44/42 MAPK (ERK1/2); PE, phenylephrine; U-0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; BQ-123, cyclo(l-Leu-d-Trp-d-Asp-l-Pro-d-Val); BQ-788, N-cis-2,6-dimethylpiperidinocarbonyl-l-yMeLeu-d-Trp(COOMe)-d-Nle-Ona; Ro-31-8220, 3-[1-(3-(amidinothio) propyl-1H-indol-3-yl)]-3-(1-methyl-1H-indol-3-yl) maleimide (bisindolylmaleimide IX); SB-203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; GF 109203X, 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride; MKP-1, mitogen-activated protein kinase phosphatase-1; COX, cyclooxygenase; FITC, fluorescein isothiocyanate; WT, wild-type; MCA, middle cerebral artery; 5-HT, 5-hydroxytryptamine; MEK, ERK MAPK kinase; MKK3/6, p38 MAPK kinase; PKC, protein kinase C; SMC, smooth muscle cell; siRNA, small interfering RNA.

    • Received July 3, 2007.
    • Accepted September 10, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (6)
Molecular Pharmacology
Vol. 72, Issue 6
1 Dec 2007
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Research ArticleArticle

Transforming Growth Factor-β1 Impairs Endothelin-1-Mediated Contraction of Brain Vessels by Inducing Mitogen-Activated Protein (MAP) Kinase Phosphatase-1 and Inhibiting p38 MAP Kinase

Xin-Kang Tong and Edith Hamel
Molecular Pharmacology December 1, 2007, 72 (6) 1476-1483; DOI: https://doi.org/10.1124/mol.107.039602

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Research ArticleArticle

Transforming Growth Factor-β1 Impairs Endothelin-1-Mediated Contraction of Brain Vessels by Inducing Mitogen-Activated Protein (MAP) Kinase Phosphatase-1 and Inhibiting p38 MAP Kinase

Xin-Kang Tong and Edith Hamel
Molecular Pharmacology December 1, 2007, 72 (6) 1476-1483; DOI: https://doi.org/10.1124/mol.107.039602
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