Mechanisms of TGF-β 1 –Induced Intimal Growth

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Abstract
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 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.