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Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-05-1685.
Submitted May 29, 2003
Accepted August 21, 2003
The in vitro and in vivo effect 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, and Abd Al-Roof Higazi*
Departments of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Clinical Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel
Department of Medicine, Hadassah Hospital, Mt. Scopus, Jerusalem, Israel
* Corresponding author; email: higazi{at}mail.med.upenn.edu.
Tissue type plasminogen activator (tPA) is a key enzymes in the fibrinolytic cascade. In the present paper we report that tPA contains two independent epitopes that exert opposite effects on blood vessel tone. Low concentrations of tPA (1nM) inhibit the phenylephrine-induced contraction of isolated aorta rings. In contrast, higher concentrations (20nM) stimulate the contractile effect of PE. The two 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, stimulate PE-induced vasoconstriction at all concentrations used. The stimulatory, but not the inhibitory effect, of tPA on contraction of isolated aorta rings was abolished by anti-low density lipoprotein receptor-related protein/ 2-macroglobulin receptor (LRP) antibodies. Administration of 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.
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