Vascular smooth muscle cells potentiate plasmin generation by both urokinase and tissue plasminogen activator-dependent mechanisms: evidence for a specific tissue-type plasminogen activator receptor on these cells.
Plasminogen activators play a role in the response of the vessel wall to injury, presumably by mediating the degradation of extracellular matrix (ECM) by vascular smooth muscle cells (VSMCs) that is necessary for their migration and proliferation. We have therefore investigated the ability of VSMCs to assemble specific cell surface plasminogen-activating systems. Urokinase-type plasminogen activator (uPA) bound to a single class of site on VSMCs (kd, 2 nmol/L), binding of pro-uPA resulted in a large potentiation of plasmin generation and both were competed by antibodies to the uPA receptor (uPAR). Tissue-type plasminogen activator (tPA) also bound to VSMCs as determined by functional assay, with the binding isotherms showing two classes of binding site with apparent kds of 25 and 300 nmol/L. tPA binding to the higher affinity site caused a greater than 90-fold enhancement of the activation of cell bound plasminogen, whereas the lower affinity binding, mediated primarily by the ECM, had little effect on tPA activity. The high-affinity binding of tPA to VSMCs resulted in an eightfold greater potential for plasmin generation than the binding of uPA, with this difference increasing to 15-fold after thrombin stimulation of the cells due to a 1.8-fold increase in tPA binding. These data show a novel specific tPA receptor on VSMCs that may be important for the regulation of plasminogen activation in various vascular pathologies.
Ellis
V
V
Thrombosis Research Institute, London, UK.
Whawell
S A
SA
D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005341:Fibrinolysin / Q000096:biosynthesis*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013917:Thrombin / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D055293:Receptors, Urokinase Plasminogen Activator; D013917:Thrombin; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator