Published Online
on March 20, 2003

A more recent version of this article appeared on April 1, 2003

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Submitted on September 10, 2002
Accepted on September 24, 2002

Abnormal Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Brain Arteriovenous Malformations

Tomoki Hashimoto MD; Gen Wen MD; Michael T. Lawton MD; Nancy J. Boudreau PhD; Andrew W. Bollen MD, DVM; Guo-Yuan Yang MD, PhD; Nicholas M. Barbaro MD; Randall T. Higashida MD; Christopher F. Dowd MD; Van V. Halbach MD; William L. Young MD^*; and for the University of California, San Francisco BAVM Study Group

From the Departments of Anesthesia and Perioperative Care (T.H., G.W., G-Y.Y., W.L.Y.), Neurological Surgery (M.T.L., N.M.B., R.T.H., C.F.D., V.V.H., W.L.Y.), Surgery (N.J.B.), Pathology (A.W.B.), Radiology (R.T.H., C.F.D.), and Neurology (W.L.Y.), and the Center for Cerebrovascular Research (T.H., G.W., G-Y.Y., W.L.Y.), University of California, San Francisco.

^* To whom correspondence should be addressed. E-mail: ccr{at}anesthesia.ucsf.edu.

Background and Purpose--Excessive degradation of the vascular matrix by matrix metalloproteinases (MMPs) can lead to structural instability of vessels. In this study we examined the expression of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in brain arteriovenous malformations (BAVMs).

Methods--We performed gelatin zymography for MMPs and Western blot for MMP-9, MMP-2, TIMP-1, TIMP-2, TIMP-3, and TIMP-4. MMP-9 expression was localized by immunohistochemistry.

Results--We analyzed 37 BAVM specimens and 9 control brain specimens from epilepsy surgery. Thirty-two BAVM patients had embolization treatment before resection. Eighteen BAVM patients had a history of hemorrhage from BAVMs. Neither MMP-2 nor TIMP-2 was detected in BAVMs or control brain specimens. Compared with control brain samples, BAVM samples had higher levels of total MMP-9, active MMP-9, pro-MMP-9, TIMP-1, and TIMP-3. TIMP-4 levels were higher in the control brain than in BAVM specimens. MMP-9 was localized to the endothelial cell/peri-endothelial cell layer and infiltrating neutrophils of BAVMs. BAVMs with venous stenosis 50% had higher expression of MMP-9 than BAVMs with venous stenosis <50%. There was no apparent association between total MMP-9, pro-MMP-9, or active MMP-9 levels and (1) feeding artery pressure, (2) pattern of draining vein (exclusively deep venous drainage versus any superficial drainage), and (3) BAVM size.

Conclusions--We found increased levels of MMP-9 and TIMPs in BAVMs. Abnormal balance of MMP-9 and TIMPs may contribute to vascular instability of BAVMs.

Key words: angiogenesis • cerebral aneurysm • cerebral arteriovenous malformations • subarachnoid hemorrhage • vascular diseases

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