Decreased type II type I TGF-beta receptor ratio in cells derived from human atherosclerotic lesions - Conversion from an antiproliferative to profibrotic response to TGF-beta 1

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-beta 1, a potent wound healing agent, and show little induction of collagen synthesis to TGF-beta 1, yet cells grown from human vascular lesions are growth stimulated by TGF-beta 1 and markedly increase collagen synthesis, Both cell types increase plasminogen activator inhibitor-1 production, switch actin phenotypes in response to TGF-beta 1, and produce similar levels of TGF-P activity, Membrane cross-linking of I-125-TGF-beta 1 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 LI TGF-beta 1 receptor mRNA is reduced in lesion cells, Transfection of the type II receptor into lesion cells restores the growth inhibitory response to TGF-P1, implying that signaling remains responsive, Because TGF-P1 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-beta 1 receptor dysfunction may be relevant for atherosclerosis, restenosis, and related fibroproliferative diseases.