Elevated intraluminal pressure inhibits vascular tissue plasminogen activator secretion and downregulates its gene expression

Lena Selin Sjögren, Roya Doroudi, Li Ming Gan, Lennart Jungersten, Thórdís Hrafnkelsdóttir, Sverker Jern*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


We recently discovered that patients with essential hypertension have a markedly impaired capacity for stimulated release of tissue plasminogen activator (tPA) from vascular endothelium. This defect may reduce the chance of timely spontaneous thrombolysis in case of an atherothrombotic event. We now investigated whether increased intraluminal pressure as such may depress vascular tPA release or downregulate its gene expression. Segments of human umbilical veins were studied in a new computerized vascular perfusion model under steady laminar flow conditions for 3 or 6 hours. Paired segments were perfused at high or physiological intraluminal pressure (40 versus 20 mm Hg) under identical shear Stress (10 dyne/cm2). Quantitative immunohistochemical evaluation of cellular tPA immunoreactivity was performed on paraffin- embedded 5-μm vascular sections. tPA mRNA in endothelial cells was quantified with reverse transcription real-time TaqMan polymerase chain reaction with GAPDH as endogenous control. Secretion of tPA into perfusion medium was evaluated with SDS-PAGE and Western blotting, followed by densitometric quantification. High-pressure perfusion downregulated tPA gene expression with a 38% decrease in tPA mRNA levels (P=0.01) compared with vessels perfused under normal intraluminal pressure, tPA release into the perfusion medium was markedly suppressed by high pressure (P<0.01 ANOVA). The intracellular storage pool of tPA was reduced after 6 but not 3 hours. Thus, elevated intraluminal pressure downregulates tPA gene and protein expression and inhibits its release from the endothelium independently of shear stress. The defective capacity for stimulated tPA release that we demonstrated in patients with essential hypertension might thus be an effect of the elevated intraluminal pressure per se.

Original languageEnglish
Pages (from-to)1002-1008
Number of pages7
Issue number4
Publication statusPublished - Apr 2000

Other keywords

  • Endothelium
  • Fibrinolysis
  • Gene expression
  • Plasminogen activators


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