TRANSFORMING GROWTH-FACTOR-BETA CONTROLS CELL-MATRIX INTERACTION OF MICROVASCULAR DERMAL ENDOTHELIAL-CELLS BY DOWN-REGULATION OF INTEGRIN EXPRESSION

Transforming growth factor-beta (TGF-beta) is a pleiotropic regulatory factor of tissue remodeling. Angiogenesis, a prerequisite of tissue r epair and tissue expansion, is induced by TGF-beta in vivo, while prol iferation and migration of cultured endothelial cells are inhibited by TGF-beta. Indirect mechanisms stimulating angiogenesis and modificati on of TGF-beta effects by cell-matrix interaction have been postulated to account for this paradigm. Because cellular behavior in tissue rem odeling is decisively determined by cell-matrix interactions, which in turn is mediated via integrins, we investigated the effect of TGF-bet a on matrix-dependent endothelial cell functions. Integrin expression of human dermal microvascular endothelial cells (HDMEC) was measured b y Northern blot and fluorescence-activated cell sorter analysis after TGF-beta treatment and correlated to cell-matrix interactions, which w ere studied in a colorimetric cell attachment assay as well as the Boy den chamber chemotaxis assay, We found a cell-specific downregulation of integrin expression in HDMEC on the level of mRNA as well as on the cell surface. This effect correlated well with the reduction of integ rin-dependent cell adhesion to several matrix proteins, in particular to fibronectin. Moreover, TGF-beta decreased fibronectin-induced chemo taxis of HDMEC. Thus, TGF-beta controls cell-matrix interaction of HDM EC by downregulation of integrin expression. This effect of TGF-beta r eflects direct and cell-specific control mechanisms on microvascular c ells that may be critical for the coordinated process of angiogenesis requiring a balance of stimulatory and inhibitory factors.