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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:737.)
© 2006 American Heart Association, Inc.

Vascular Biology

Transforming Growth Factor Beta 1 Induces Neointima Formation Through Plasminogen Activator Inhibitor-1–Dependent Pathways

Goro Otsuka; Ramtin Agah; Andrew D. Frutkin; Thomas N. Wight; David A. Dichek

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.

Correspondence to David A. Dichek, MD, Department of Medicine, University of Washington, Box 357710, 1959 NE Pacific St, Seattle, WA 98195-7710. E-mail ddichek{at}u.washington.edu

Objective— The mechanisms through which transforming growth factor (TGF)-ß1 promotes intimal growth, and the pathways through which TGF-ß1 expression is regulated in the artery wall, are incompletely understood. We used a mouse model to investigate mechanisms of TGF-ß1–induced intimal growth.

Methods and Results— Adenovirus-mediated overexpression of TGF-ß1 in uninjured carotid arteries of wild-type mice induced formation of a cellular and matrix-rich intima. Intimal growth appeared primarily due to cell migration and matrix accumulation, with only a negligible contribution from cell proliferation. Overexpression of TGF-ß1 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-ß1–induced intimal growth, we transduced carotid arteries of PAI-1–deficient (Serpine1^–/–) mice with the TGF-ß1–expressing vector. Overexpression of TGF-ß1 in Serpine1^–/– arteries did not increase intimal growth, matrix accumulation, cell migration, or proliferation. Moreover, TGF-ß1–transduced arteries of Serpine1^–/– mice secreted 6- to 10-fold more TGF-ß1 than did arteries of wild-type mice that were infused with the same concentration of the TGF-ß1–expressing vector.

Conclusions— PAI-1 is both a critical mediator of TGF-ß1–induced intimal growth and a key negative regulator of TGF-ß1 expression in the artery wall.

We investigated mechanisms of TGF-ß1–induced intimal growth. TGF-ß1 induced neointimal formation through cell migration and matrix accumulation. Overexpression of TGF-ß1 in arteries of PAI-1–deficient mice revealed that PAI-1 is both a critical mediator of TGF-ß1–induced intimal growth and a key negative regulator of TGF-ß1 expression in the artery wall.

Key Words: carotid arteries • gene transfer • intima • plasminogen activator inhibitor-1 • TGF-beta

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PAI-1 and TGF-ß: Unmasking the Real Driver of TGF-ß–Induced Vascular Pathology

Douglas E. Vaughan
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