Decreased type II/type I TGF-β receptor ratio in cells derived from human atherosclerotic lesions: Conversion from an antiproliferative to profibrotic response to TGF-β1

Abstract

Atherosclerosis and postangioplasty restenosis may result from abnormal wound healing. The present studies report that normal human smooth muscle cells are growth inhibited by TGF-β1, a potent wound healing agent, and show little induction of collagen synthesis to TGF-β1, yet cells grown from human vascular lesions are growth stimulated by TGF-β1 and markedly increase collagen synthesis. Both cell types increase plasminogen activator inhibitor-1 production, switch actin phenotypes in response to TGF-β1, and produce similar levels of TGF-β activity. Membrane cross-linking of 125I-TGF-β1 indicates that normal human smooth muscle cells express type I, II, and III receptors. The type II receptor is strikingly decreased in lesion cells, with little change in the type I or III receptors. RT-PCR confirmed that the type II TGF-β1 receptor mRNA is reduced in lesion cells. Transfection of the type II receptor into lesion cells restores the growth inhibitory response to TGF-β1, implying that signaling remains responsive. Because TGF-β1 is overexpressed in fibroproliferative vascular lesions, receptor-variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components. This TGF-β1 receptor dysfunction may be relevant for atherosclerosis, restenosis, and related fibroproliferative diseases.