title: Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester.
abstract: 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 alpha (TNF alpha). 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 TNF alpha or interleukin 1 alpha (IL-1 alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNF alpha 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 TNF alpha 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.
authors.affiliation: Gaubius Laboratory IVVO-TNO, Leiden, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Hanemaaijer
authors.forename: P
authors.initials: P
authors.lastname: Koolwijk
authors.forename: L
authors.initials: L
authors.lastname: le Clercq
authors.forename: W J
authors.initials: WJ
authors.lastname: de Vree
authors.forename: V W
authors.initials: VW
authors.lastname: van Hinsbergh
mesh_terms: D002196:Capillaries / Q000201:enzymology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology*; D004790:Enzyme Induction; D005109:Extracellular Matrix / Q000201:enzymology*; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014680:Veins / Q000201:enzymology
chemical_list: D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate