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Reactive site‐dependent phenotypic alterations in plasminogen activator inhibitor‐1 transgenic mice

Summary.  Background: Plasminogen activator inhibitor‐1 (PAI‐1) is the major physiological inhibitor of plasminogen activators (PAs) and plays a role in the regulation of a number of physiological processes including the degradation of extracellular matrix proteins, cell proliferation and migration, and intracellular signaling. Aim: To characterize the effects of durable expression of a stable form of human PAI‐1 and to characterize important structure–function relationships in PAI‐1 in vivo.Methods: We developed transgenic mice lines overexpressing stable variants of human PAI‐1 under the control of the murine preproendothelin‐1 promoter and characterized the phenotypic alterations displayed by transgenic mice. Results: Transgenic mice expressing an active form of human PAI‐1 (PAI‐1‐stab) display complex phenotypic abnormalities including alopecia and hepatosplenomegaly. Reactive site mutant transgenic mice expressing inactive PAI‐1 exhibit complete phenotypic rescue, while transgenic mice expressing PAI‐1 with reduced affinity for vitronectin manifest all of the phenotypic abnormalities present in PAI‐1‐stab transgenic mice. Conclusions: The protease inhibitory activity of PAI‐1 toward PAs and/or other serine proteases is necessary and sufficient to promote complex phenotypic abnormalities and mediates many of the physiological effects of PAI‐1 in vivo.