Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells: Effects of tumour necrosis factor α, interleukin 1 and phorbol ester

Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascular endothelial cells, and compared these data with those obtained with human synovial fibroblasts. Non-stimulated vein endothelial cells expressed 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 stimulated by the inflammatory mediator tumour necrosis factor α (TNFα). The expression of MMP-3 and MMP-1 was further enhanced by phorbol 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNFα or interleukin 1α (IL-1α). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNFα induces/enhances the production of several matrix metalloproteinases in human endothelial cells. On the other hand, MMP-2 and TIMP-2 were not affected or were affected in a variable way by TNFα and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the production of MMPs in a cell-type-specific way. In human vein endothelial cells it enhanced the PMA-mediated induction of MMP-9, whereas it suppressed this induction in human microvascular endothelial cells and in synovial fibroblasts. On the other hand, forskolin suppressed the PMA-mediated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human endothelial cells. These observations may have implications for future pharmacological intervention in angiogenesis. Chemicals/CAS: collagenase, 37288-86-1, 39433-96-0, 9001-12-1; forskolin, 66575-29-9; gelatinase B, 146480-36-6; gelatinase, 9040-48-6; matrilysin, 141256-52-2; metalloproteinase, 81669-70-7; phorbol 12 acetate 13 myristate, 31365-46-5; protein, 67254-75-5; stromelysin, 79955-99-0; tissue inhibitor of metalloproteinase, 97837-28-0; Forskolin, 66428-89-5; Interleukin-1; Metalloendopeptidases, EC 3.4.24; RNA, Messenger; Tetradecanoylphorbol Acetate, 16561-29-8; Tumor Necrosis Factor