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Plasminogen activator inhibitor-1 impairs plasminogen activation-mediated vascular smooth muscle cell apoptosis

Patrick Rossignol1, Eduardo Anglès-Cano, Henri Roger Lijnen

  • 1Center for Molecular and Vascular Biology, K.U.Leuven, Leuven, Belgium.

Thrombosis and Haemostasis
|November 3, 2006
PubMed

Insights

Plasminogen activator inhibitor-1 (PAI-1) impairs plasmin-mediated apoptosis in vascular smooth muscle cells (VSMCs). Reducing PAI-1 accelerates VSMC apoptosis via plasminogen activation by tissue-type (t-PA) or urokinase-type (u-PA) plasminogen activators.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cardiovascular Research

Background:

  • Vascular smooth muscle cell (VSMC) apoptosis plays a critical role in cardiovascular diseases.
  • Plasminogen activation system components, including plasminogen activator inhibitor-1 (PAI-1), are implicated in VSMC biology.
  • The precise role of PAI-1 in VSMC apoptosis mediated by plasminogen activation remains to be fully elucidated.

Purpose of the Study:

  • To investigate the role of plasminogen activator inhibitor-1 (PAI-1) in vascular smooth muscle cell (VSMC) apoptosis.
  • To determine how PAI-1 influences plasminogen activation and subsequent apoptotic processes in VSMCs.
  • To compare apoptosis rates in VSMCs with and without PAI-1, and with deficiencies in tissue-type (t-PA) or urokinase-type (u-PA) plasminogen activators.

Main Methods:

  • Utilized aortic VSMCs from PAI-1 deficient (PAI-1 (-/-)), t-PA deficient (t-PA (-/-)), u-PA deficient (u-PA (-/-)), and wildtype (WT) mice.
  • Assessed plasminogen activation rates on VSMC surfaces.
  • Quantified VSMC apoptosis using morphological analysis and apoptotic index measurements after incubation with plasminogen.

Main Results:

  • Plasminogen activation on VSMCs was concentration-dependent and saturable, with higher rates observed in PAI-1 (-/-) cells compared to WT, t-PA (-/-), or u-PA (-/-) cells.
  • Plasminogen activation was dependent on cell surface COOH-terminal lysine residues and plasminogen activator activity.
  • PAI-1 (-/-) VSMCs exhibited significantly earlier and higher rates of apoptosis when incubated with plasminogen, correlating with plasmin release.

Conclusions:

  • Plasmin-mediated apoptosis of VSMCs occurs through plasminogen activation by either t-PA or u-PA.
  • Plasminogen activator inhibitor-1 (PAI-1) significantly impairs plasmin-mediated VSMC apoptosis.
  • These findings highlight PAI-1 as a key regulator of VSMC apoptosis in the context of plasminogen activation.

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