Mechanisms of TGF-β1–Induced Intimal Growth: Plasminogen-Independent Activities of Plasminogen Activator Inhibitor-1 and Heterogeneous Origin of Intimal Cells

• Published in: Circulation research Vol. 100; no. 9; pp. 1300 - 1307
• Main Authors: Otsuka, Goro, Stempien-Otero, April, Frutkin, Andrew D, Dichek, David A
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 11.05.2007; Lippincott
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Vertebrates: cardiovascular system; Plasminogen activator inhibitor 1; Vertebrata; Mammalia; plasminogen activator inhibitor-1; β1. intima; Growth; Transforming growth factor; Intima; Circulatory system; Transforming growth factor β1; Plasminogen; Cell origin
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000266970.34017.8d

Transforming growth factor (TGF)-β1 is a potent stimulator of intimal growth. We showed previously that TGF-β1 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-β1 expression in the artery wall. Here we use plasminogen-deficient mice to test whether TGF-β1–stimulated, PAI-1–dependent intimal growth and PAI-1 suppression of TGF-β1 expression are mediated through inhibition of plasminogen activation by PAI-1. We also use lineage tracing to investigate the origin of cells in TGF-β1–induced intimas. Surprisingly, both TGF-β1–induced, PAI-1–dependent intimal growth and PAI-1 suppression of TGF-β1 expression are independent of plasminogen. Moreover, approximately 50% of cells that migrate into the intima of TGF-β1–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-β1 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-β1 activation in the artery wall. Further identification of the molecular targets through which PAI-1 stimulates intimal formation and suppresses TGF-β1 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-β1 recruits intimal cells and suggest instead that TGF-β1 induces substantial cell migration either from the adventitia or from an extravascular, but nonhematopoietic source.