title: Hemodynamic forces modulate the effects of cytokines on fibrinolytic activity of endothelial cells.
abstract: We investigated the effects of hemodynamic force on fibrinolytic activity of cultured human umbilical vein endothelial cells stimulated by cytokines, using a modified cone-plate viscometer in which well-controlled and -defined shear forces were generated. Treatment of the cells with interleukin (IL)-beta or tumor necrosis factor alpha (TNFalpha) under static conditions had no effect on tissue plasminogen activator (t-PA) secretion, while release of plasminogen activator inhibitor 1 (PAI-1) increased. When cells were exposed to increasing shear stress up to 24 dynes/cm2, levels of t-PA and t-PA/PAI-1 complex significantly increased relative to shear stress, while total PAI-1 and active PAI-1 secretion decreased gradually. In the presence of IL-1beta or TNFalpha, the increase in production of t-PA and the t-PA/PAI-1 complex was further augmented. Dot blot hybridization analysis of cultured cells in similar experimental conditions using t-PA and PAI-1 cDNA probes revealed no t-PA mRNA in 3 microg total RNA from static endothelial cells under resting or cytokine-stimulated conditions, but abundant t-PA mRNA was detected in cells subjected to a shear force of 18 dynes/cm2, and the increase was further augmented by addition of cytokines. In contrast, PAI-1 mRNA was detected in resting and cytokine-stimulated, nonsheared endothelial cells, but levels decreased after exposure to shear stress, even in the presence of cytokines. These results indicate a role for hemodynamic forces in regulating fibrinolytic activity with or without cytokine stimulation.
authors.affiliation: Departments of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawai
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Satoh
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: M
authors.initials: M
authors.lastname: Handa
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005342:Fibrinolysis / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018056:Hemorheology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D013314:Stress, Mechanical; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins
chemical_list: D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D010959:Tissue Plasminogen Activator