STRUCTURAL HETEROGENEITY OF THE DIFFUSE INTIMAL THICKENING AND CORRELATION WITH DISTRIBUTION OF TGF-BETA(1)

This study examines the ultrastructural features of diffuse intimal thickenings of human coronary arteries and correlates structural heterogeneity along the radial axis with the distribution and known actions of transforming growth factor beta1 (TGF-beta1). Morphometric and immunohistochemical data were collected from thickenings of varying widths, sampled at autopsy from 19 persons ranging in age from 3 months to 81 years. Thickenings were characterised by an inner proteoglycan layer (PGL), up to approximately 70 mm wide, and an underlying variable-width musculofibrous layer (MFL). The PGL was characterised by low volume fractions (v/fs) for collagen, elastin, basement membranes and cells and a high v/f for matrix space; v/fs for the MFL components were more evenly distributed. Proteoglycans were visualised by ruthenium red staining, quantified and sized. Densities of large (versican; >20 nm) and small (<20 nm) granules changed little across intimal thickenings. Mean diameters of matrix space granules increased with increasing intimal thickness and notably were significantly (p<0.001) larger in the PGL than the MFL. In contrast, diameters of collagen-associated small granules (decorin) did not differ between the PGL and MFL. TGF-beta1 staining was detected in 70% of vessels examined and occurred almost exclusively in the PGL, although showed a patchy distribution. Both the distribution of TGF-beta1 and its known differential effects on versican and decorin synthesis suggest that it may play a significant role in the formation and maintenance of the PGL.