Distinct Patterns of Transforming Growth Factor-β Isoform and Receptor Expression in Human Atherosclerotic Lesions Colocalization Implicates TGF-β in Fibrofatty Lesion Development

• Published in: Circulation (New York, N.Y.) Vol. 99; no. 22; pp. 2883 - 2891
• Main Authors: Bobik, Alex, Agrotis, Alex, Kanellakis, Peter, Dilley, Rodney, Krushinsky, Anatoly, Smirnov, Vladimir, Tararak, Eduard, Condron, Melanie, Kostolias, Gina
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 08.06.1999; American Heart Association, Inc
• Subjects: Activin Receptors, Type I; Adult; Aged; Aorta - metabolism; Aorta - pathology; Arteriosclerosis - metabolism; Arteriosclerosis - pathology; Female; Fibrosis; Humans; Immunohistochemistry; Isomerism; Male; Microsatellite Repeats; Middle Aged; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Protein-Serine-Threonine Kinases - metabolism; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Reference Values; Tissue Distribution - physiology; Transforming Growth Factor beta - metabolism
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/01.CIR.99.22.2883

Background —Some animal studies suggest that transforming growth factor-β (TGF-β) protects vessels from atherosclerosis by preventing intima formation, but others indicate a role in vessel proteoglycan accumulation and lipoprotein retention. To distinguish between these possibilities in humans, immunohistochemical studies were performed examining the coexpression of TGF-β isoforms and the TGF-β receptors ALK-5 and TβR-II in aorta during the various stages of atherosclerotic lesion development. Methods and Results —The spatial relationships between TGF-β 1 , TGF-β 3 , ALK-5, and TβR-II expression were compared in aortic segments from 21 subjects. Nonatherosclerotic intima contained predominantly TGF-β 1 , low concentrations of TβR-II, and barely detectable amounts of ALK-5. In contrast, fatty streaks/fibrofatty lesions contained high concentrations of both TGF-β isoforms. Smooth muscle cells (SMCs), macrophages, and foam cells of macrophage and SMC origin contributed to these high levels. These lesions also contained high, colocalized concentrations of ALK-5 and TβR-II. Despite fibrous plaques containing TGF-β 1 , its receptors were at detection limits. We found no evidence for truncated TβR-II expression in either normal intima or the various atherosclerotic lesions. Conclusions —TGF-β appears to be most active in lipid-rich aortic intimal lesions. The findings support the hypothesis that TGF-β contributes primarily to the pathogenesis of lipid-rich atherosclerotic lesions by stimulating the production of lipoprotein-trapping proteoglycans, inhibiting smooth muscle proliferation, and activating proteolytic mechanisms in macrophages.