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

J Thromb Haemost. 2007 Jul;5(7):1500-8. doi: 10.1111/j.1538-7836.2007.02587.x. Epub 2007 Apr 16.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • DNA Primers / genetics
  • Female
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Phenotype
  • Plasminogen Activator Inhibitor 1 / chemistry
  • Plasminogen Activator Inhibitor 1 / genetics*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Skin / metabolism
  • Skin / pathology
  • Tissue Distribution


  • DNA Primers
  • Plasminogen Activator Inhibitor 1
  • Recombinant Proteins
  • SERPINE1 protein, human