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 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, <1% carry a bone marrow lineage marker, and the remaining cells carry neither marker. Therefore, PAI-1 stimulates intimal growth and suppresses TGF-beta(1) 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-beta(1) activation in the artery wall. Further identification of the molecular targets through which PAI-1 stimulates intimal formation and suppresses TGF-beta(1) 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-beta(1) recruits intimal cells and suggest instead that TGF-beta(1) induces substantial cell migration either from the adventitia or from an extravascular, but nonhematopoietic source.
Otsuka
Goro
G
Department of Medicine, University of Washington, Seattle, WA 98195-7710, USA.
Stempien-Otero
April
A
Frutkin
Andrew D
AD
Dichek
David A
DA
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010958:Plasminogen / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D019700:Thrombospondin 1 / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology
D017395:Plasminogen Activator Inhibitor 1; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D010958:Plasminogen