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      Plasmin-Mediated Fibroblast Growth Factor-2 Mobilisation Supports Smooth Muscle Cell Proliferation in Human Saphenous Vein


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          The focus of this study was identification of the contribution of the plasminogen activator-plasmin system to smooth muscle cell proliferation and migration in human saphenous vein. Segments of human saphenous vein were grown in organ culture for up to 14 days. Smooth muscle cell proliferation and migration were measured by incubating vein segments in bromodeoxyuridine, and smooth muscle cell death was detected by in situ end-labelling. Tissue-type (tPA) and urokinase-type (uPA) plasminogen activator enzymic activities were detectable in cultured saphenous vein segments, and were concentrated in focal zones. Inhibition of plasmin activity with α-N-acetyl- L-lysine methyl ester (NALME) or of uPA activity with a neutralising antibody caused significant decreases in smooth muscle cell proliferation in the media and the intima, but no significant changes in smooth muscle cell migration. Intimal thickness was also significantly decreased. Incubation with plasminogen or plasmin caused fibroblast growth factor-2 (FGF2) to be released into the medium. Addition of FGF2 to segments cultured with NALME reversed the inhibition of smooth muscle cell proliferation, and blocking the activity of FGF2 with a neutralising antibody caused a significant decrease in medial smooth muscle cell proliferation. These data suggest that plasmin mobilises FGF2 bound to the extracellular matrix of human saphenous vein, so that it can support smooth muscle cell proliferation and intimal thickening.

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          Most cited references7

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          Proteoglycans as modulators of growth factor activities.

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            Thrombospondin-1 Is a Major Activator of TGF-β1 In Vivo

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              Amiloride selectively inhibits the urokinase-type plasminogen activator.

              The diuretic drug amiloride, an inhibitor of Na+ uptake, competitively inhibits the catalytic activity of the urokinase-type plasminogen activator (u-PA), with a Ki of 7 X 10(-6) M. Generation of plasmin, cleavage of peptide substrates, and interaction of u-PA with a specific macromolecular proteinase inhibitor are all prevented in the presence of the drug. In contrast, amiloride does not affect the activity of either tissue-type plasminogen activator, plasmin, plasma kallikrein or thrombin. The inhibition of u-PA by amiloride may be related to the previously reported inhibition of u-PA-type enzymes by Na+. Amiloride or related compounds could prove useful in selectively controlling u-PA-catalyzed extracellular proteolysis.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2001
                17 September 2001
                : 38
                : 5
                : 492-501
                Bristol Heart Institute, University of Bristol, Bristol, UK
                51082 J Vasc Res 2001;38:492–501
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 3, References: 41, Pages: 10
                Research Paper

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Fibroblast growth factor,Extracellular matrix,Saphenous vein,Bypass graft,Plasmin,Smooth muscle cell


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