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(Circulation Research. 2007;100:1300.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Mechanisms of TGF-ß₁–Induced Intimal Growth

Plasminogen-Independent Activities of Plasminogen Activator Inhibitor-1 and Heterogeneous Origin of Intimal Cells

Goro Otsuka, April Stempien-Otero, Andrew D. Frutkin, David A. Dichek

From the Department of Medicine, University of Washington, Seattle.

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

Transforming growth factor (TGF)-ß₁ is a potent stimulator of intimal growth. We showed previously that TGF-ß₁ 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-ß₁ expression in the artery wall. Here we use plasminogen-deficient mice to test whether TGF-ß₁–stimulated, PAI-1–dependent intimal growth and PAI-1 suppression of TGF-ß₁ expression are mediated through inhibition of plasminogen activation by PAI-1. We also use lineage tracing to investigate the origin of cells in TGF-ß₁–induced intimas. Surprisingly, both TGF-ß₁–induced, PAI-1–dependent intimal growth and PAI-1 suppression of TGF-ß₁ expression are independent of plasminogen. Moreover, approximately 50% of cells that migrate into the intima of TGF-ß₁–overexpressing arteries carry a smooth muscle lineage marker, <1% carry a bone marrow lineage marker, and the remaining cells carry neither marker. Therefore, PAI-1 stimulates intimal growth and suppresses TGF-ß₁ expression through activities other than inhibition of plasminogen activation. In addition, contrary to widely held models, our results do not support a role for plasmin (or thrombospondin) in TGF-ß₁ activation in the artery wall. Further identification of the molecular targets through which PAI-1 stimulates intimal formation and suppresses TGF-ß₁ expression in the artery wall may reveal new approaches for inhibiting intimal formation. Our studies also discount bone marrow as an important source from which TGF-ß₁ recruits intimal cells and suggest instead that TGF-ß₁ induces substantial cell migration either from the adventitia or from an extravascular, but nonhematopoietic source.

Key Words: plasminogen activator inhibitor-1 • plasminogen • transforming growth factor ß₁ • intima

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