Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice

J Thromb Haemost. 2007 Aug;5(8):1732-9. doi: 10.1111/j.1538-7836.2007.02628.x. Epub 2007 May 21.


Background: Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke.

Objectives: To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke.

Methods: Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg(-/-)), stromelysin-1 (MMP-3(-/-)), or gelatinase B (MMP-9(-/-)) and their corresponding wild-type (WT) littermates. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice.

Results: ICB induced by t-PA (10 mg kg(-1)) was significantly less than WT in Plg(-/-) (P < 0.05) and MMP-3(-/-) (P < 0.05) but not in MMP-9(-/-) mice. Furthermore, administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly (P < 0.05) in MMP-3(+/+) mice, but had no effect on MMP-3(-/-) mice. MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was up-regulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment.

Conclusions: Our data with gene-deficient mice thus suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation*
  • Intracranial Hemorrhages / enzymology*
  • Intracranial Hemorrhages / etiology
  • Ischemia / complications
  • Matrix Metalloproteinase 3 / physiology*
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Genetic
  • Neurons / metabolism
  • Placebos
  • Stroke / blood*
  • Stroke / complications
  • Stroke / drug therapy*
  • Thrombolytic Therapy / methods
  • Tissue Plasminogen Activator / therapeutic use*


  • Placebos
  • Tissue Plasminogen Activator
  • Matrix Metalloproteinase 3
  • Mmp3 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse