Distinct Patterns of Transforming Growth Factor-β Isoform and Receptor Expression in Human Atherosclerotic Lesions

Abstract

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.