on December 22, 2005
Published online before print December 22, 2005, doi: 10.1161/01.ATV.0000201087.23877.e1
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Submitted on July 6, 2005
Accepted on December 7, 2005
Transforming Growth Factor Beta 1 Induces Neointima Formation Through Plasminogen Activator Inhibitor-1-Dependent Pathways
Goro Otsuka ;
From the Department of Medicine (G.O., A.D.F., D.A.D.) University of Washington, Seattle, Wash; the Hope Heart Program (T.N.W.), Benaroya Research Institute at Virginia Mason, Seattle, Wash; and the Gladstone Institute of Cardiovascular Disease (R.A., D.A.D.), University of California, San Francisco, Calif.
* To whom correspondence should be addressed. E-mail: ddichek{at}u.washington.edu.
Objective--The mechanisms through which transforming growth factor (TGF)-
1 promotes intimal growth, and the pathways through which TGF-1 expression is regulated in the artery wall, are incompletely understood. We used a mouse model to investigate mechanisms of TGF-1-induced intimal growth.
Methods and Results--Adenovirus-mediated overexpression of TGF-1 in uninjured carotid arteries of wild-type mice induced formation of a cellular matrix-rich intima. Intimal growth appeared primarily because of cell migration and matrix accumulation, with only a negligible contribution from cell proliferation. Overexpression of TGF-1 also stimulated expression of plasminogen activator inhibitor type 1 (plasminogen activator inhibitor [PAI]-1) in the artery wall. To test the hypothesis that PAI-1 is a critical downstream mediator of TGF-1-induced intimal growth, we transduced carotid arteries of PAI-1-deficient (Serpine1-/-) mice with the TGF-1-expressing vector. Overexpression of TGF-1 in Serpine1-/- arteries did not increase intimal growth, matrix accumulation, cell migration, or proliferation. Moreover, TGF-1-transduced arteries of Serpine1-/- mice secreted 6- to 10-fold more TGF-1 than did arteries of wild-type mice that were infused with the same concentration of the TGF-1-expressing vector.
Conclusions--PAI-1 is both a critical mediator of TGF-1-induced intimal growth and a key negative regulator of TGF-1 expression in the artery wall.
Key words: carotid arteries • gene transfer • intima • plasminogen activator inhibitor-1 • TGF-beta
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