Vascular extracellular matrix remodeling in cerebral aneurysms.
OBJECTIVE
The occurrence of cerebral aneurysms has been linked to alterations in the extracellular matrix and to matrix-degrading proteases. The purpose of the present study was to determine whether active extracellular matrix remodeling occurs within cerebral aneurysms.


METHODS
Aneurysm tissue was collected from 23 patients (two of whom had a ruptured aneurysm and 21 of whom had an unruptured aneurysm) and compared with 11 control basilar arteries harvested at autopsy. Active proteinases capable of gelatin lysis were identified by performing in situ zymography in the presence and absence of a metalloproteinase inhibitor (ethylenediamine tetraacetic acid) and a serine proteinase inhibitor (phenylmethylsulfonyl fluoride). Immunohistochemical analysis was used to localize plasmin, tissue-type (t)-plasminogen activator (PA), urokinase-type (u)-PA, membranetype (MT1)-matrix metalloproteinase (MMP), MMP-2, MMP-9, and tenascin. Focal areas of gelatin lysis occurred in most cerebral aneurysm tissue samples (17 of 21), but rarely in control arteries (two of 11) (p = 0.002). Both serine proteinases and MMPs contributed to gelatin lysis; however, the MMPs were the predominant enzyme family. Plasmin (p = 0.04) and MT1-MMP (p = 0.04) were expressed in the aneurysm tissue but were unusual in control tissue. The MMP-2 was also expressed more commonly in aneurysm than in control tissue (p = 0.07). The MMP-9 and t-PA were expressed in both groups; however, different staining patterns were observed between aneurysm and control tissue. Tenascin staining was commonly present in both groups, whereas u-PA staining was rarely present.


CONCLUSIONS
Aneurysm tissue demonstrates increased proteolytic activity capable of lysing gelatin and increased expression of plasmin, MT1-MMP, and MMP-2 when compared with normal cerebral arteries. This activity may contribute to focal degradation of the vascular extracellular matrix and may be related to aneurysm formation and growth.
Bruno
G
G
Cerebrovascular Research Laboratory, The Cleveland Clinic Foundation, Ohio 44195, USA.
Todor
R
R
Lewis
I
I
Chyatte
D
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017542:Aneurysm, Ruptured / Q000201:enzymology / Q000473:pathology; D001488:Basilar Artery / Q000033:anatomy & histology / Q000201:enzymology; D017364:Collagenases / Q000032:analysis; D004492:Edetic Acid; D010450:Endopeptidases / Q000032:analysis; D004791:Enzyme Inhibitors; D005109:Extracellular Matrix / Q000201:enzymology / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000032:analysis*; D005260:Female; D005341:Fibrinolysin / Q000032:analysis; D005343:Fibrinolytic Agents / Q000032:analysis; D018093:Gelatinases / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D002532:Intracranial Aneurysm / Q000201:enzymology / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors; D008875:Middle Aged; D010664:Phenylmethylsulfonyl Fluoride; D010960:Plasminogen Activators / Q000032:analysis; D012697:Serine Endopeptidases / Q000032:analysis; D015842:Serine Proteinase Inhibitors; D019063:Tenascin / Q000032:analysis; D010959:Tissue Plasminogen Activator / Q000032:analysis; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis
D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D005343:Fibrinolytic Agents; D015842:Serine Proteinase Inhibitors; D019063:Tenascin; D010664:Phenylmethylsulfonyl Fluoride; D004492:Edetic Acid; D010450:Endopeptidases; D010960:Plasminogen Activators; D012697:Serine Endopeptidases; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D017364:Collagenases; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9