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  • Title: Transforming growth factor beta 1 induces neointima formation through plasminogen activator inhibitor-1-dependent pathways.
    Author: Otsuka G, Agah R, Frutkin AD, Wight TN, Dichek DA.
    Journal: Arterioscler Thromb Vasc Biol; 2006 Apr; 26(4):737-43. PubMed ID: 16373605.
    Abstract:
    OBJECTIVE: The mechanisms through which transforming growth factor (TGF)-beta1 promotes intimal growth, and the pathways through which TGF-beta1 expression is regulated in the artery wall, are incompletely understood. We used a mouse model to investigate mechanisms of TGF-beta1-induced intimal growth. METHODS AND RESULTS: Adenovirus-mediated overexpression of TGF-beta1 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-beta1 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-beta1-induced intimal growth, we transduced carotid arteries of PAI-1-deficient (Serpine1(-/-)) mice with the TGF-beta1-expressing vector. Overexpression of TGF-beta1 in Serpine1(-/-) arteries did not increase intimal growth, matrix accumulation, cell migration, or proliferation. Moreover, TGF-beta1-transduced arteries of Serpine1(-/-) mice secreted 6- to 10-fold more TGF-beta1 than did arteries of wild-type mice that were infused with the same concentration of the TGF-beta1-expressing vector. CONCLUSIONS: PAI-1 is both a critical mediator of TGF-beta1-induced intimal growth and a key negative regulator of TGF-beta1 expression in the artery wall.
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