title: 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-beta1.
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-beta1, a potent wound healing agent, and show little induction of collagen synthesis to TGF-beta1, yet cells grown from human vascular lesions are growth stimulated by TGF-beta1 and markedly increase collagen synthesis. Both cell types increase plasminogen activator inhibitor-1 production, switch actin phenotypes in response to TGF-beta1, and produce similar levels of TGF-beta activity. Membrane cross-linking of 125I-TGF-beta1 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-beta1 receptor mRNA is reduced in lesion cells. Transfection of the type II receptor into lesion cells restores the growth inhibitory response to TGF-beta1, implying that signaling remains responsive. Because TGF-beta1 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-beta1 receptor dysfunction may be relevant for atherosclerosis, restenosis and related fibroproliferative diseases.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Cornell University Medical College, New York Hospital, New York 10021, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: McCaffrey
authors.forename: S
authors.initials: S
authors.lastname: Consigli
authors.forename: B
authors.initials: B
authors.lastname: Du
authors.forename: D J
authors.initials: DJ
authors.lastname: Falcone
authors.forename: T A
authors.initials: TA
authors.lastname: Sanborn
authors.forename: A M
authors.initials: AM
authors.lastname: Spokojny
authors.forename: H L
authors.initials: HL
authors.lastname: Bush
mesh_terms: D000199:Actins / Q000096:biosynthesis; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D003327:Coronary Disease / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000096:biosynthesis / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012016:Reference Values; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: D000199:Actins; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D017395:Plasminogen Activator Inhibitor 1; D011509:Proteoglycans; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C071736:betaglycan; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D001616:beta-Galactosidase