Abstract
Urokinase plasminogen activator (uPA) is a multifunctional protein that has been implicated in several physiological and pathological processes involving cell adhesion and migration in addition to fibrinolysis. In a previous study we found that two-chain urokinase plasminogen activator (tcuPA) stimulates phenylephrine-induced vasoconstriction of isolated rat aortic rings. In the present paper we report that uPA(-/-) mice have a significantly lower mean arterial blood pressure than do wild type mice and that aortic rings from uPA(-/-) mice show an attenuated contractile response to phenylephrine. In contrast, the blood pressure of urokinase receptor knockout (uPAR(-/-)) mice and the response of their isolated aortic rings to phenylephrine were normal, indicating that the effect of uPA on vascular contraction is independent of uPAR. Addition of mouse and human uPA almost completely reversed both the impaired vascular contractility and the lower arterial blood pressure in vivo. The in vitro and in vivo effects of infused uPA on aortic contractility and the restoration of normal blood pressure in uPA(-/-) mice were prevented by antibody to low-density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor (LRP). A modified form of uPA that lacks the kringle failed to restore the blood pressure in uPA(-/-) mice, notwithstanding having a longer half-life in the circulation. Ligands that regulate the interaction of uPA with LRP, such as PAI-1 or the PAI-1-derived peptide (EEIIMD), abolished the vasoactivity of tcuPA in vitro and in vivo. These studies identify a novel signal transducing cellular receptor pathway involved in the regulation of vascular contractility.
Highlights
Urokinase plasminogen activator1 is a multifunctional protein that has been implicated in several physiological and pathological processes, including fibrinolysis
In a previous study we found that two-chain urokinase plasminogen activator stimulates phenylephrine-induced vasoconstriction of isolated rat aortic rings
We report that the stimulatory effect of two-chain urokinase plasminogen activator (tcuPA) on vascular smooth muscle cell activation is mediated by lipoprotein receptor-related protein/␣2-macroglobulin receptor (LRP) and through a process that inhibited by Plasminogen activator inhibitor type 1 (PAI-1) but independent of its proteolytic activity
Summary
Urokinase plasminogen activator (uPA) is a multifunctional protein that has been implicated in several physiological and pathological processes, including fibrinolysis. The possibility that uPA contributes to the regulation of vascular tone may help to explain some of the phenotypic changes described in uPAϪ/Ϫ mice and perhaps provide a broader understanding of the role played by uPA in certain physiological and pathological processes, such as inflammation [6] and metastasis. It was, of interest to examine the contribution of endogenous uPA to the regulation of vasoactivity in vivo. We report that the stimulatory effect of tcuPA on vascular smooth muscle cell activation is mediated by LRP and through a process that inhibited by PAI-1 but independent of its proteolytic activity
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