In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone

Taher Nassar, Sa'ed Akkawi, Ahuva Shina, Abdullah Haj-Yehia, Khalil Bdeir, Mark Tarshis, Samuel N. Heyman, Abd Al Roof Higazi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Tissue type plasminogen activator (tPA) is a key enzyme in the fibrinolytic cascade. In this paper we report that tPA contains 2 independent epitopes that exert opposite effects on blood vessel tone. Low concentrations of tPA (1 nM) inhibit the phenylephrine (PE)-induced contraction of isolated aorta rings. In contrast, higher concentrations (20 nM) stimulate the contractile effect of PE. The 2 putative vasoactive epitopes of tPA are regulated by the plasminogen activator inhibitor-1 (PAI-1) and by a PAI-1-derived hexapeptide that binds tPA. TNK-tPA, a tPA variant in which the PAI-1 docking site has been mutated, stimulates PE-induced vasoconstriction at all concentrations used. The stimulatory, but not the inhibitory, effect of tPA on the contraction of isolated aorta rings was abolished by anti-low-density lipoprotein receptor-related protein/α2-macroglobulin receptor (LRP) antibodies. Administering tPA or TNK-tPA to rats regulates blood pressure and cerebral vascular resistance in a dose-dependent mode. In other in vivo experiments we found that the vasopressor effect of PE is more pronounced in tPA knockout than in wild-type mice. Our findings draw attention to a novel role of tPA and PAI-1 in the regulation of blood vessel tone that may affect the course of ischemic diseases.

Original languageAmerican English
Pages (from-to)897-902
Number of pages6
JournalBlood
Volume103
Issue number3
DOIs
StatePublished - 1 Feb 2004

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