Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats.
OBJECTIVE
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.
Aoki
Tomohiro
T
Kyoto University, Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, Japan.
Kataoka
Hiroharu
H
Morimoto
Masafumi
M
Nozaki
Kazuhiko
K
Hashimoto
Nobuo
N
D000818:Animals; D002536:Cerebral Arteries / Q000201:enzymology* / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D002532:Intracranial Aneurysm / Q000201:enzymology* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014657:Vasculitis / Q000201:enzymology / Q000503:physiopathology
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9