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J. Biol. Chem., Vol. 282, Issue 51, 37244-37255, December 21, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/51/37244    most recent M708137200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lagna, G. Articles by Hata, A. Search for Related Content PubMed PubMed Citation Articles by Lagna, G. Articles by Hata, A. Social Bookmarking                      What's this?

Control of Phenotypic Plasticity of Smooth Muscle Cells by Bone Morphogenetic Protein Signaling through the Myocardin-related Transcription Factors^*

Giorgio Lagna¹, Manching M. Ku, Peter H. Nguyen, Nicole A. Neuman, Brandi N. Davis, and Akiko Hata

From the Molecular Cardiology Research Institute, Tufts-New England Medical Center and the Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111

Vascular smooth muscle cells (VSMCs), unlike other muscle cells, do not terminally differentiate. In response to injury, VSMCs change phenotype, proliferate, and migrate as part of the repair process. Dysregulation of this plasticity program contributes to the pathogenesis of several vascular disorders, such as atherosclerosis, restenosis, and hypertension. The discovery of mutations in the gene encoding BMPRII, the type II subunit of the receptor for bone morphogenetic proteins (BMPs), in patients with pulmonary arterial hypertension (PAH) provided an indication that BMP signaling may affect the homeostasis of VSMCs and their phenotype modulation. Here we report that BMP signaling potently induces SMC-specific genes in pluripotent cells and prevents dedifferentiation of arterial SMCs. The BMP-induced phenotype switch requires intact RhoA/ROCK signaling but is not blocked by inhibitors of the TGFβ and PI3K/Akt pathways. Furthermore, nuclear localization and recruitment of the myocardin-related transcription factors (MRTF-A and MRTF-B) to a smooth muscle -actin promoter is observed in response to BMP treatment. Thus, BMP signaling modulates VSMC phenotype via cross-talk with the RhoA/MRTFs pathway, and may contribute to the development of the pathological characteristics observed in patients with PAH and other obliterative vascular diseases.

Received for publication, October 1, 2007 , and in revised form, October 16, 2007.

^* This work was supported by NHLBI (National Institutes of Health) (to A. H.) and the American Heart Association (to G. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: MCRI, Tufts-New England Medical Center, 750 Washington St., Box 8486, Boston, MA 02111. Tel.: 617-636-4994; Fax: 617-636-5649; E-mail: glagna{at}tufts-nemc.org.

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