Mechanisms of TGF-beta1-induced intimal growth: plasminogen-independent activities of plasminogen activator inhibitor-1 and heterogeneous origin of intimal cells

Transforming growth factor (TGF)-beta(1) is a potent stimulator of intimal growth. We showed previously that TGF-beta(1) stimulates intimal growth through early upregulation of plasminogen activator inhibitor-1 (PAI-1) and, subsequently, PAI-1-dependent increases in cell migration and matrix accumul...

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Bibliographic Details
Published in:Circulation research 2007-05, Vol.100 (9), p.1300-1307
Main Authors: Otsuka, Goro, Stempien-Otero, April, Frutkin, Andrew D, Dichek, David A
Format: Article
Language:English
Subjects:
Animals
Cell Movement
Cell Proliferation
Male
Mice
Mice, Inbred C57BL
Plasminogen - physiology
Plasminogen Activator Inhibitor 1 - physiology
Thrombospondin 1 - physiology
Transforming Growth Factor beta1 - genetics
Transforming Growth Factor beta1 - physiology
Tunica Intima - pathology
Tunica Media - pathology
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Summary:Transforming growth factor (TGF)-beta(1) is a potent stimulator of intimal growth. We showed previously that TGF-beta(1) stimulates intimal growth through early upregulation of plasminogen activator inhibitor-1 (PAI-1) and, subsequently, PAI-1-dependent increases in cell migration and matrix accumulation. We also showed that PAI-1 negatively regulates TGF-beta(1) expression in the artery wall. Here we use plasminogen-deficient mice to test whether TGF-beta(1)-stimulated, PAI-1-dependent intimal growth and PAI-1 suppression of TGF-beta(1) expression are mediated through inhibition of plasminogen activation by PAI-1. We also use lineage tracing to investigate the origin of cells in TGF-beta(1)-induced intimas. Surprisingly, both TGF-beta(1)-induced, PAI-1-dependent intimal growth and PAI-1 suppression of TGF-beta(1) expression are independent of plasminogen. Moreover, approximately 50% of cells that migrate into the intima of TGF-beta(1)-overexpressing arteries carry a smooth muscle lineage marker,
ISSN:1524-4571