TGF-beta1 generates a specific multicomponent extracellular matrix in human coronary SMC.

BACKGROUND

Transforming growth factor (TGF-beta(1)) is postulated to play an important role in maintaining the structure and function of arterial tissue and protection against development of arteriosclerosis. The TGF-beta(1)-induced production of a stable extra-cellular matrix-rich plaque phenotype is suggested to be part of the protection against a switch to an unstable rupture-prone arteriosclerotic plaque.

MATERIALS AND METHODS

This study addresses the question of whether the expression profile and the type of extra-cellular matrix (ECM) generated by TGF-beta(1) stimulation have the structural feature of a fibril-rich stable matrix. Seventeen genes codings for ECM components of human coronary smooth muscle cells (SMCs) after a 24-h stimulation by TGF-beta(1) have been analyzed.

RESULTS

Real-time RT-PCR was used to quantify the mRNA of genes under investigation. It was found that after TGF-beta(1) stimulation (a) the up-regulation of COL1A1-specific mRNA was associated with increased [(3)H]proline incorporation into the alpha-1 and -2 chains of collagen type I, (b) the up-regulation of biglycan- and syndecan-1-specific mRNA corresponded to an increased [(35)S]sulphate and [4,5-(3)H]leucine incorporation into the biglycan molecule and to an increase of syndecan-1 protein, (c) the up-regulated FGF-2 gene accounted predominantly for the ECM-bound subfraction of FGF-2-protein and (d) fibronectin and thrombospondin exhibited a significantly higher mRNA level. In contrast collagen XIV, a minor collagen type, and the proteoglycan decorin were down-regulated. The down-regulated decorin changed its structure by elongation and reduced GlcA to IdoA epimerization of the dermatan sulphate side-chain as judged by [(35)S]sulphate metabolic labelling experiments. No significant changes in response to TGF-beta(1) were observed for the collagen types III, VI and XVI, for versican, perlecan and the syndecans-2 and -4.

CONCLUSIONS

It was concluded from the data that the TGF-beta(1)-induced formation of a highly specific multicomponent extra-cellular matrix on coronary arterial SMCs could provide in vivo mechanical strength to the neointima in arteriosclerotic lesions and to the fibrous cap overlying the lipid core.