Distinct patterns of transforming growth factor-β isoform and receptor expression in human atherosclerotic lesions -: Colocalization implicates TGF-β in fibrofatty lesion development

Background-Some animal studies suggest that transforming growth factor-beta (TGF-beta) 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-beta isoforms and the TGF-beta receptors ALK-5 and T beta R-II in aorta during the various stages of atherosclerotic lesion development. Methods and Results-The spatial relationships between TGF-beta(1), TGF-beta(3), ALK-5, and T beta R-II expression were compared in aortic segments from 21 subjects. Nonatherosclerotic intima contained predominantly TGF-beta(1), low concentrations of T beta R-II, and barely detectable amounts of ALK-5, In contrast, fatty streaks/fibrofatty lesions contained high concentrations of both TGF-beta 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 T beta R-II. Despite fibrous plaques containing TGF-beta(1). its receptors were at detection limits. We found no evidence for truncated T beta R-II expression in either normal intima or the various atherosclerotic lesions. Conclusions-TGF-beta appears to be most active in lipid-rich aortic intimal lesions. The findings support the hypothesis that TGF-beta 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.