Vascular extracellular matrix remodeling in cerebral aneurysms.

OBJECT 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.

[1]  P. Libby,et al.  Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. , 1997, Circulation.

[2]  G. Butler,et al.  Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases. , 1997, European journal of biochemistry.

[3]  L N Sekhar,et al.  Origin, growth, and rupture of saccular aneurysms: a review. , 1981, Neurosurgery.

[4]  P. Mignatti.  Extracellular matrix remodeling by metalloproteinases and plasminogen activators. , 1995, Kidney international. Supplement.

[5]  H. Oxlund,et al.  Collagen type III deficiency in patients with rupture of intracranial saccular aneurysms. , 1987, Journal of neurosurgery.

[6]  J. Reilly,et al.  Possible key role for plasmin in the pathogenesis of abdominal aortic aneurysms. , 1994, Surgery.

[7]  G. Sicard,et al.  Abnormal expression of plasminogen activators in aortic aneurysmal and occlusive disease. , 1994, Journal of vascular surgery.

[8]  L. Brandt,et al.  Causes of unfavorable outcome after early aneurysm operation. , 1983, Neurosurgery.

[9]  B. Sobel,et al.  Modulation of expression of monocyte/macrophage plasminogen activator activity and its implications for attenuation of vasculopathy. , 1994, Circulation.

[10]  G. Forbes,et al.  Interobserver variability in angiographic measurement and morphologic characterization of intracranial aneurysms: a report from the International Study of Unruptured Intracranial Aneurysms. , 1996, AJNR. American journal of neuroradiology.

[11]  R. Ross.  The pathogenesis of atherosclerosis: a perspective for the 1990s , 1993, Nature.

[12]  H. Adams,et al.  Influence of Timing of Admission After Aneurysmal Subarachnoid Hemorrhage On Overall Outcome: Report of the Cooperative Aneurysm Study , 1981, Stroke.

[13]  M. Cubellis,et al.  The receptor for urokinase‐plasminogen activator , 1986, Journal of cellular biochemistry.

[14]  E. Connolly,et al.  Matrix metalloproteinase-9 in cerebral aneurysms. , 1997, Neurosurgery.

[15]  M. Chiquet,et al.  Regulation of extracellular matrix synthesis by mechanical stress. , 1996, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[16]  J. Bartlett,et al.  Collagen deficiency and ruptured cerebral aneurysms. A clinical and biochemical study. , 1983, Journal of neurosurgery.

[17]  W. Penfield.  EPILEPSY, THE GREAT TEACHER , 1967 .

[18]  L. Brandt,et al.  Early operation and overall outcome in aneurysmal subarachnoid hemorrhage. , 1985, Journal of neurosurgery.

[19]  E. Connolly,et al.  Serum elastase and alpha-1-antitrypsin levels in patients with ruptured and unruptured cerebral aneurysms. , 1995, Neurosurgery.

[20]  P. Libby,et al.  Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. , 1994, The Journal of clinical investigation.

[21]  V. Kakkar,et al.  Plasminogen activator expression in human atherosclerotic lesions. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[22]  T. Sundt,et al.  Early versus late intracranial aneurysm surgery in subarachnoid hemorrhage. , 1988, Journal of neurosurgery.

[23]  P. Delvenne,et al.  Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms. , 1996, Journal of vascular surgery.

[24]  W. Stetler-Stevenson,et al.  MMP-2: expression, activation and inhibition. , 1996, Enzyme & protein.

[25]  A. Kugler.  Matrix metalloproteinases and their inhibitors. , 1999, Anticancer research.

[26]  J. McEwan,et al.  Matrix metalloproteinases and cardiovascular disease. , 1995, Circulation research.

[27]  C. Bauters,et al.  Restenosis after coronary angioplasty. , 1995, European heart journal.

[28]  D. Rifkin,et al.  Biology and biochemistry of proteinases in tumor invasion. , 1993, Physiological reviews.

[29]  J. Scholes,et al.  The elastase infusion model of experimental aortic aneurysms: synchrony of induction of endogenous proteinases with matrix destruction and inflammatory cell response. , 1994, Journal of vascular surgery.

[30]  P. Libby,et al.  Enhanced Expression of Vascular Matrix Metalloproteinases Induced In Vitro by Cytokines and in Regions of Human Atherosclerotic Lesions a , 1994, Annals of the New York Academy of Sciences.

[31]  M. D. Tilson,et al.  Morphometric analysis of reticular and elastin fibers in the cerebral arteries of patients with intracranial aneurysms. , 1990, Neurosurgery.

[32]  V. Ellis,et al.  Mechanisms of plasminogen activation , 1994, Journal of internal medicine.

[33]  M. Seiki,et al.  Intermolecular Autolytic Cleavage Can Contribute to the Activation of Progelatinase A by Cell Membranes (*) , 1995, The Journal of Biological Chemistry.

[34]  T. Sundt,et al.  Subarachnoid hemorrhage from intracranial aneurysms. Surgical management and natural history of disease. , 1978, The New England journal of medicine.

[35]  R. Kandolf,et al.  Mechanismen der Re-Stenosierung nach Angioplastie , 1994 .

[36]  L. Zanetta,et al.  Control of type IV collagenase activity by components of the urokinase–plasmin system: a regulatory mechanism with cell‐bound reactants , 1997, The EMBO journal.

[37]  K. Schmid,et al.  Quantification of plasminogen activators and their inhibitors in the aortic vessel wall in relation to the presence and severity of atherosclerotic disease. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[38]  G. Butler,et al.  The Soluble Catalytic Domain of Membrane Type 1 Matrix Metalloproteinase Cleaves the Propeptide of Progelatinase A and Initiates Autoproteolytic Activation , 1996, The Journal of Biological Chemistry.

[39]  R. Warnke,et al.  Suppression of endogenous avidin-binding activity in tissues and its relevance to biotin-avidin detection systems. , 1981, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[40]  R. Ross.  Cellular and molecular studies of atherogenesis. , 1997, Atherosclerosis.

[41]  E. Reske‐Nielsen,et al.  Histological and morphometric observations on the reticular fibers in the arterial beds of patients with ruptured intracranial saccular aneurysms. , 1987, Neurosurgery.

[42]  Y. Okada,et al.  Cell surface binding and activation of gelatinase A induced by expression of membrane‐type‐1‐matrix metalloproteinase (MT1‐MMP) , 1996, FEBS letters.

[43]  Z. Werb,et al.  The extracellular matrix ligands fibronectin and tenascin collaborate in regulating collagenase gene expression in fibroblasts. , 1994, Molecular biology of the cell.

[44]  Y. DeClerck,et al.  Cooperation between matrix metalloproteinases and the plasminogen activator-plasmin system in tumor progression. , 1996, Enzyme & protein.

[45]  K. Crossin,et al.  Tenascin: A multifunctional extracellular matrix protein with a restricted distribution in development and disease , 1996, Journal of cellular biochemistry.

[46]  P. Libby,et al.  Microscopic localization of active proteases by in situ zymography: detection of matrix metalloproteinase activity in vascular tissue , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[47]  J. Scholes,et al.  Cellular localization of matrix metalloproteinases in the abdominal aortic aneurysm wall. , 1994, Journal of vascular surgery.

[48]  G. Yong-zhong,et al.  Pathogenesis and histopathology of saccular aneurysms: review of the literature. , 1990, Neurological research.

[49]  J. Scholes,et al.  Matrix metalloproteinases in abdominal aortic aneurysm: characterization, purification, and their possible sources. , 1994, Connective tissue research.

[50]  S. Schenk,et al.  The complexity in regulating the expression of tenascins , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.

[51]  S. Pakarinen.  Incidence, aetiology, and prognosis of primary subarachnoid haemorrhage. A study based on 589 cases diagnosed in a defined urban population during a defined period. , 1967, Acta neurologica Scandinavica.