Transforming Growth Factor-β Controls Cell-Matrix Interaction of Microvascular Dermal Endothelial Cells by Downregulation of Integrin Expression

Abstract

Transforming growth factor-beta (TGF-beta) is a pleiotropic regulatory factor of tissue remodeling. Angiogenesis, a prerequisite of tissue repair and tissue expansion, is induced by TGF-beta in vivo, while proliferation and migration of cultured endothelial cells are inhibited by TGF-beta. Indirect mechanisms stimulating angiogenesis and modification of TGF-beta effects by cell-matrix interaction have been postulated to account for this paradigm. Because cellular behavior in tissue remodeling is decisively determined by cell-matrix interactions, which in turn is mediated via integrins, we investigated the effect of TGF-beta on matrix-dependent endothelial cell functions. Integrin expression of human dermal microvascular endothelial cells (HDMEC) was measured by Northern blot and fluorescence-activated cell sorter analysis after TGF-beta treatment and correlated to cell-matrix interactions, which were studied in a colorimetric cell attachment assay as well as the Boyden 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 integrin-dependent cell adhesion to several matrix proteins, in particular to fibronectin. Moreover, TGF-beta decreased fibronectin-induced chemotaxis of HDMEC. Thus, TGF-beta controls cell-matrix interaction of HDMEC by down-regulation of integrin expression. This effect of TGF-beta reflects direct and cell-specific control mechanisms on microvascular cells that may be critical for the coordinated process of angiogenesis requiring a balance of stimulatory and inhibitory factors.