HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/2/H540    most recent 91478.2007v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tsai, S. Articles by Kent, K. C. PubMed PubMed Citation Articles by Tsai, S. Articles by Kent, K. C.

TGF-β through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation

¹Department of Surgery, Division of Vascular Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York; and ²Department of Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin

Submitted 17 December 2007 ; accepted in final form 5 May 2009

The objective of this study was to better understand the role of transforming growth factor-β (TGF-β) and its primary signaling protein Smad3 in the development of intimal hyperplasia. Male Sprague-Dawley rats underwent left carotid balloon injury followed by intra-arterial infection with adenovirus-expressing Smad3 (AdSmad3). In uninfected injured arteries, endogenous Smad3 was upregulated with the expression peaking at 14 days. Moreover, in arteries infected with AdSmad3, we observed an enhancement of intimal hyperplasia and increased vascular smooth muscle cell (VSMC) proliferation. The novel finding, that TGF-β/Smad3 stimulated rather than inhibited VSMC proliferation, was confirmed in cultured VSMCs infected with AdSmad3 and treated with TGF-β. To identify the mechanism underlying TGF-β/Smad3-mediated VSMC proliferation, we studied the cyclin-dependent kinase inhibitor p27. Although the upregulation of Smad3 in VSMCs had no significant effect on total p27 levels, Smad3 did stimulate the phosphorylation of p27 at serine-10 as well as the nuclear export of p27, events associated with cell proliferation. Furthermore, serine-10-phosphorylated p27 was also increased in AdSmad3-infected injured rat carotid arteries, demonstrating the existence of this same mechanism in vivo. In conclusion, our findings identify a novel mechanism for the effect of TGF-β on intimal hyperplasia. In the presence of elevated levels of Smad3 that develop in response to injury, TGF-β stimulates smooth muscle cell proliferation through a mechanism involving the phosphorylation and nuclear export of p27.

serine-10-phosphorylated p27; rat carotid balloon injury