Skip Navigation



Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 1, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp220
This Article
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
84/2/326    most recent
cvp220v2
cvp220v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Kundi, R.
Right arrow Articles by Kent, K. C.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kundi, R.
Right arrow Articles by Kent, K. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Arterial gene transfer of the TGFβ signaling protein Smad3 induces adaptive remodeling following angioplasty: a role for CTGF

Rishi Kundi, M.D., Scott T. Hollenbeck, M.D., Dai Yamanouchi, M.D., Ph.D.*, Brad Herman, Ph.D., Rachel Edlin, Evan J. Ryer, M.D., Chunjie Wang, Shirling Tsai, M.D., Bo Liu, Ph.D.* and K. Craig Kent, M.D.*

Division of Vascular Surgery, Weill Medical College of Cornell University, Columbia College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY
* Department of Surgery, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin

Address correspondence and reprint requests to: Bo Liu, Ph.D. Department of Surgery, University of Wisconsin Madison, 1111 Highland Avenue, WIMR 5137, Madison, WI 53705, Tel: (608)-265-5139, FAX: (608)-262-3333, Email: liub{at}surgery.wisc.edu

AIM: While Transforming growth factor-beta (TGFβ) is believed to stimulate intimal hyperplasia after arterial injury, its role in remodeling remains unclear. We investigate whether Smad3, a TGFβ signaling protein, might facilitate its effect on remodeling.

METHODS: Using the rat carotid angioplasty model, we assess Smad3 expression following arterial injury. We then test the effect of arterial Smad3 overexpression on the response to injury, and use a conditioned media experimental design to confirm a Smad3-dependent soluble factor that mediates this response. We use small interfering RNA to identify this factor as connective tissue growth factor (CTGF). Finally, we attempt to replicate the effect of medial Smad3 overexpression through adventitial application of recombinant CTGF.

RESULTS: Injury induced medial expression of Smad3; overexpression of Smad3 caused neointimal thickening and luminal expansion, suggesting adaptive remodeling. Smad3 overexpression, though exclusively medial, caused adventitial changes: myofibroblast transformation, proliferation and collagen production, all of which are associated with adaptive remodeling. Supporting the hypothesis that Smad3 initiated remodeling and these adventitial changes via a secreted product of medial smooth muscle cells (SMCs), we found that media conditioned by Smad3-expressing recombinant adenoviral vector (AdSmad3) infected SMCs stimulated adventitial fibroblast transformation, proliferation, and collagen production in vitro. This effect was attenuated by pretreatment of SMCs with siRNA specific for CTGF, abundantly produced by AdSmad3-infected SMCs, and significantly upregulated in Smad3-overexpressing arteries. Moreover, periadventitial administration of CTGF replicated the effect of medial Smad3 overexpression on adaptive remodeling and neointimal hyperplasia.

CONCLUSIONS: Medial gene transfer of Smad3 promotes adaptive remodeling by indirectly influencing the behavior of adventitial fibroblasts. This arterial cell-cell communication is likely to be mediated by Smad3-dependent production of CTGF.

KEYWORDS TGF-beta; Smad3; connective tissue growth factor; restenosis; remodeling; adventitia

Time for primary review: 36 Days

Classifications: experimental / vasculature / cellular / multicellular / organ / molecular biology / pathophysiology / angioplasty / growth factors / remodeling / restenosis


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.