Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats

Stroke. 2007 Jan;38(1):162-9. doi: 10.1161/01.STR.0000252129.18605.c8. Epub 2006 Nov 22.


Background and purpose: Mechanisms of initiation, progression and rupture of cerebral aneurysms have not yet been fully understood despite its clinical significance. Matrix metalloproteinases (MMPs) are a family of proteinases which are involved in the remodeling of vascular walls. In the present study, we investigated the significance of MMPs in the progression of cerebral aneurysms.

Methods: Cerebral aneurysms were experimentally induced in 7-week-old male Sprague-Dawley rats. MMP-2 and MMP-9 expression was examined by immunohistochemistry and RT-PCR. Gelatinase activity in aneurysmal walls was assessed by in situ zymography. A selective inhibitor for MMP-2, -9 and -12, tolylsam, was used to examine the effect of inhibition of MMP-2 and MMP-9.

Results: Macrophages infiltrated in arterial walls of experimentally induced rat cerebral aneurysms and expressed MMP-2 and -9. Macrophage infiltration and MMP expression was increased with the progression of aneurysms. Gelatinase activity attributable to MMP-2 and MMP-9 increased in arterial walls of rat cerebral aneurysms. Furthermore, tolylsam reduced the ratio of advanced aneurysms in our rat model.

Conclusions: These data suggest that macrophage-derived MMP-2 and -9 may play an important role in the progression of cerebral aneurysms. The findings of this study will shed a new light into the pathogenesis of cerebral aneurysms and highlight the importance of inflammatory response causing the degeneration of extracellular matrix in the process of this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Arteries / enzymology*
  • Cerebral Arteries / physiopathology
  • Chemotaxis, Leukocyte / drug effects
  • Chemotaxis, Leukocyte / physiology
  • Disease Models, Animal
  • Disease Progression
  • Enzyme Inhibitors / pharmacology
  • Immunohistochemistry
  • Intracranial Aneurysm / enzymology*
  • Intracranial Aneurysm / physiopathology
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / metabolism
  • Male
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase Inhibitors
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vasculitis / enzymology
  • Vasculitis / physiopathology


  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9