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

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Abstract
Objective— The mechanisms through which transforming growth factor (TGF)-β1 promotes intimal growth, and the pathways through which TGF-β1 expression is regulated in the artery wall, are incompletely understood. We used a mouse model to investigate mechanisms of TGF-β1–induced intimal growth. Methods and Results— Adenovirus-mediated overexpression of TGF-β1 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-β1 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-β1–induced intimal growth, we transduced carotid arteries of PAI-1–deficient (Serpine1−/−) mice with the TGF-β1–expressing vector. Overexpression of TGF-β1 in Serpine1−/− arteries did not increase intimal growth, matrix accumulation, cell migration, or proliferation. Moreover, TGF-β1–transduced arteries of Serpine1−/− mice secreted 6- to 10-fold more TGF-β1 than did arteries of wild-type mice that were infused with the same concentration of the TGF-β1–expressing vector. Conclusions— PAI-1 is both a critical mediator of TGF-β1–induced intimal growth and a key negative regulator of TGF-β1 expression in the artery wall. We investigated mechanisms of TGF-β1–induced intimal growth. TGF-β1 induced neointimal formation through cell migration and matrix accumulation. Overexpression of TGF-β1 in arteries of PAI-1–deficient mice revealed that PAI-1 is both a critical mediator of TGF-β1–induced intimal growth and a key negative regulator of TGF-β1 expression in the artery wall.