REGULATION OF MATRIX METALLOPROTEINASE EXPRESSION IN HUMAN VEIN AND MICROVASCULAR ENDOTHELIAL-CELLS - EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA, INTERLEUKIN-1 AND PHORBOL ESTER

Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of M MP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromely sin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascu lar endothelial cells, and compared these data with those obtained wit h human synovial fibroblasts. Non-stimulated vein endothelial cells ex pressed the mRNAs for MMP-1, MMP-2, TIMP-1 and TIMP-2. MMP-3 mRNA and protein were undetectable or only weakly expressed, but could be stimu lated by the inflammatory mediator tumour necrosis factor alpha (TNFal pha). The expression of MMP-3 and MMP-1 was further enhanced by phorbo l 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNFalph a or interleukin 1alpha (IL-1alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory me diator TNFalpha induces/enhances the production of several matrix meta lloproteinases in human endothelial cells. On the other hand, MMP-2 an d TIMP-2 were not affected or were affected in a variable way by TNFal pha and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the produc tion of MMPs in a cell-type-specific way. In human vein endothelial ce lls it enhanced the PMA-mediated induction of MMP-9, whereas it suppre ssed this induction in human microvascular endothelial cells and in sy novial fibroblasts. On the other hand, forskolin suppressed the PMA-me diated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human en dothelial cells. These observations may have implications for future p harmacological intervention in angiogenesis.