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Blood, 1 February 2004, Vol. 103, No. 3, pp. 897-902.
Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-05-1685.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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, and
Abd Al-Roof Higazi
From the Departments of Clinical Biochemistry and Medicine, Hadassah Hospital, Mt Scopus, Israel; Interdepartmental Unit and School of Pharmacy, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel; and the Departments of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
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/ 2-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.
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