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Plasminogen activator inhibitor-1 impairs plasminogen activation-mediated vascular smooth muscle cell apoptosis: : PAI-1 and plasminogen-induced VSMC apoptosis

Abstract : The role of plasminogen activator inhibitor-1 (PAI-1) in vascular smooth muscle cell (VSMC) apoptosis mediated by plasminogen activation was studied with the use of aortic VSMC derived from mice with deficiency of PAI-1 (PAI-1-/-), tissue-type (t-PA-/-) or urokinase-type (u-PA-/-) plasminogen activator or from wild-type (WT) mice with corresponding genetic background. Plasminogen incubated with confluent VSMC was activated in a concentration-dependent and saturable manner for all 4 cell types, with maximal activation rates that were comparable for WT, u-PA-/- and t-PA-/- cells, but about 2- fold higher for PAI-1-/- cells. Plasminogen activation was impaired by addition of the lysine analogue 6-aminohexanoic acid, and by addition of t-PA and u-PA neutralizing antibodies, suggesting that it depends on binding to cell surface COOH-terminal lysine residues, and on plasminogen activator activity. Morphological alterations consistent with apoptosis were observed much earlier in PAI-1-/- than in WT VSMC. Without addition of plasminogen, the apoptotic index was similar for all 4 cell types, whereas after incubation with physiological plasminogen concentrations, it was greater in PAI-1-/- VSMC, as compared to WT, t-PA-/- or u-PA-/- VSMC. Furthermore, the apoptotic rate paralleled the release of plasmin. Thus, plasmin-mediated apoptosis of VSMC occurs via plasminogen activation by either t-PA or u-PA and is impaired by PAI-1.
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https://www.hal.inserm.fr/inserm-00160754
Contributor : Eduardo Angles-Cano <>
Submitted on : Monday, July 9, 2007 - 12:59:07 PM
Last modification on : Wednesday, October 14, 2020 - 4:07:53 AM
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Patrick Rossignol, Eduardo Angles-Cano, Henri Roger Lijnen. Plasminogen activator inhibitor-1 impairs plasminogen activation-mediated vascular smooth muscle cell apoptosis: : PAI-1 and plasminogen-induced VSMC apoptosis. Thrombosis and Haemostasis, Schattauer, 2006, 96 (5), pp.665-670. ⟨10.1160/TH06-06-0321⟩. ⟨inserm-00160754⟩

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