Prolonged cyclic strain impairs the fibrinolytic system in cultured vascular endothelial cells.
OBJECTIVE
We previously reported that patients with primary hypertension have an impaired ability to release tissue-type plasminogen activator acutely from the vascular endothelium, and recently found that lowering blood pressure can restore this capacity. We hypothesized that the suppression of the fibrinolytic system is caused by the chronic pressure-induced increased haemodynamic load on the endothelium.


METHODS
This study investigated the effect of the tensile force component of blood pressure by exposing cultured human aortic endothelial cells to 10% cyclic strain for 6-72 h. Messenger RNA levels of tissue-type plasminogen activator, urokinase-type plasminogen activator, and plasminogen activator inhibitor 1 were analysed using Taqman real-time reverse transcriptase-polymerase chain reaction and protein release by enzyme-linked immunosorbent assay.


RESULTS
Tensile stimulation resulted in a transient initial upregulation of tissue-type plasminogen activator mRNA at 6 h (53%), which declined with time, and at 48 h had switched to a 28% downregulation. The reduction was sustained after 72 h. Tissue-type plasminogen activator protein secretion showed a similar but somewhat delayed response, with a transient increase in release at 6 h (60%), declining to a final 12% reduction at 72 h. A similar pattern was observed for urokinase-type plasminogen activator mRNA. By contrast, plasminogen activator inhibitor 1 mRNA expression and protein secretion increased at all timepoints (16-47%).


CONCLUSIONS
Prolonged tensile stimulation impairs fibrinolytic activity in human aortic endothelial cells by a dual action, with suppression of plasminogen activator expression and increased inhibitor production. This effect of tensile stress may contribute to the reduced fibrinolytic capacity observed in patients with hypertension.
Clinical Experimental Research Laboratory, Sahlgrenska University Hospital/Ostra, the Cardiovascular Institute, Göteborg University, Göteborg, Sweden.
Erik
E
Ulfhammer
Wilhelm
W
Ridderstråle
Maria
M
Andersson
Lena
L
Karlsson
Thórdís
T
Hrafnkelsdóttir
Sverker
S
Jern
D001011:Aorta / Q000166:cytology; D002460:Cell Line; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology*; D004797:Enzyme-Linked Immunosorbent Assay; D005342:Fibrinolysis / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator