This Article Full Text Full Text (PDF) All Versions of this Article: 34/4/925    most recent 01.STR.0000061888.71524.DFv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hashimoto, T. Articles by Rosenberg, G. A. Search for Related Content PubMed PubMed Citation Articles by Hashimoto, T. Articles by Rosenberg, G. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arteriovenous Malformations Related Collections Angiogenesis Cerebral Aneurysm, AVM, & Subarachnoid hemorrhage Aneurysm, AVM, hematoma Endothelium/vascular type/nitric oxide Other Vascular biology

(Stroke. 2003;34:925.)
© 2003 American Heart Association, Inc.

Original Contributions

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 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.

Correspondence to William L. Young, MD, University of California, San Francisco, 1001 Potrero Ave, Room 3C-38, San Francisco, CA 94110. 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.

Growth and Bleeding in BAVM: Another Role for MMPs

Gary A. Rosenberg, MD, Guest Editor

This article has been cited by other articles:

				Q. Hao, H. Su, D. A. Marchuk, R. Rola, Y. Wang, W. Liu, W. L. Young, and G.-Y. Yang Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2250 - H2256. [Abstract] [Full Text] [PDF]

				K. S. Moshal, M. Singh, U. Sen, D. S. E. Rosenberger, B. Henderson, N. Tyagi, H. Zhang, and S. C. Tyagi Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2825 - H2835. [Abstract] [Full Text] [PDF]

				K. S. Moshal, U. Sen, N. Tyagi, B. Henderson, M. Steed, A. V. Ovechkin, and S. C. Tyagi Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway Am J Physiol Cell Physiol, March 1, 2006; 290(3): C883 - C891. [Abstract] [Full Text] [PDF]

				A. S. Achrol, L. Pawlikowska, C. E. McCulloch, K. Y. T. Poon, C. Ha, J. G. Zaroff, S. C. Johnston, C. Lee, M. T. Lawton, S. Sidney, et al. Tumor Necrosis Factor-{alpha}-238G>A Promoter Polymorphism Is Associated With Increased Risk of New Hemorrhage in the Natural Course of Patients With Brain Arteriovenous Malformations Stroke, January 1, 2006; 37(1): 231 - 234. [Abstract] [Full Text] [PDF]

				J. J. Marler, S. J. Fishman, S. M. Kilroy, J. Fang, J. Upton, J. B. Mulliken, P. E. Burrows, D. Zurakowski, J. Folkman, and M. A. Moses Increased Expression of Urinary Matrix Metalloproteinases Parallels the Extent and Activity of Vascular Anomalies Pediatrics, July 1, 2005; 116(1): 38 - 45. [Abstract] [Full Text] [PDF]

				C. Z. Lee, B. Xu, T. Hashimoto, C. E. McCulloch, G.-Y. Yang, and W. L. Young Doxycycline Suppresses Cerebral Matrix Metalloproteinase-9 and Angiogenesis Induced by Focal Hyperstimulation of Vascular Endothelial Growth Factor in a Mouse Model Stroke, July 1, 2004; 35(7): 1715 - 1719. [Abstract] [Full Text] [PDF]