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(Circulation Research. 2005;97:1115.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Nitric Oxide Regulates Transforming Growth Factor-ß Signaling in Endothelial Cells

Marta Saura, Carlos Zaragoza, Beatrice Herranz, Mercedes Griera, Luisa Diez-Marqués, Diego Rodriguez-Puyol, Manuel Rodriguez-Puyol

From the Departmento Fisiología (M.S., B.H., M.G., L.D.-M., M.R.-P.), Universidad de Alcalá, Alcalá de Henares; Nefrología (D.R.-P.), Hospital Príncipe de Asturias, Alcalá de Henares; and Centro Nacional de Investigaciones Cardiovasculares (C.Z.), Madrid, Spain.

Correspondence to Dr Marta Saura, Autovía Madrid-Barcelona Km 33,500, Alcalá de Henares, 28871 Madrid, Spain. E-mail marta.saura{at}uah.es

Many forms of vascular disease are characterized by increased transforming growth factor (TGF)-ß₁ expression and endothelial dysfunction. Smad proteins are a key step in TGF-ß–initiated signal transduction. We hypothesized that NO may regulate endothelial TGF-ß–dependent gene expression. We show that NO inhibits TGF-ß/Smad–regulated gene transactivation in a cGMP-dependent manner. NO effects were mimicked by a soluble analogue of cGMP. Inhibition of cGMP-dependent protein kinase 1 (PKG-1) or overexpression of dominant-negative PKG-1 suppressed NO/cGMP inhibition of TGF-ß–induced gene expression. Inversely, overexpression of PKG-1 catalytic subunit blocked TGF-ß–induced gene transactivation. Furthermore NO delayed and reduced phosphorylated Smad2/3 nuclear translocation, an effect mediated by PKG-1, whereas N^G-nitro-L-arginine methyl ester augmented Smad phosphorylation and gene expression in response to TGF-ß. Aortas from endothelial NO synthase–deficient mice showed enhanced basal TGF-ß₁ and collagen type I expression; endothelial cells from these animals showed increased Smad phosphorylation and transcriptional activity. Proteasome inhibitors prevented the inhibitory effect of NO on TGF-ß signaling. NO reduced the metabolic life of ectopically expressed Smad2 and enhanced its ubiquitination. Taken together, these results suggest that the endothelial NO/cGMP/PKG pathway interferes with TGF-ß/Smad2 signaling by directing the proteasomal degradation of activated Smad.

Key Words: nitric oxide • endothelial cells • vascular remodeling • transforming growth factor-ß

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