on August 2, 2007
Published online before print August 2, 2007, doi: 10.1161/STROKEAHA.106.481515
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 28, 2006
From the Departments of Anesthesia and Perioperative Care (C.Z.L., Z.X., Y.Z., G.-Y.Y., W.L.Y.), Neurological Surgery (G.-Y.Y., W.L.Y.), and Neurology (W.L.Y.), Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, Calif. * To whom correspondence should be addressed. E-mail: ccr{at}anesthesia.ucsf.edu.
Background and Purpose—Human brain arteriovenous malformation tissue displays increased levels of vascular endothelial growth factor (VEGF) as well as matrix metalloproteinase (MMP)-9, a tissue protease associated with various intracerebral hemorrhage (ICH). We hypothesized that increased MMP-9 was associated with ICH induced by vascular endothelial growth factor hyperstimulation and that this effect could be attenuated by nonspecific MMP inhibition. Methods—We used a mouse model with adenoviral vector-mediated vascular endothelial growth factor transduction in the brain. The association of MMP-9 expression and the brain tissue hemoglobin levels, an index of ICH, after stereotactic injection of adenoviral vector-mediated vascular endothelial growth factor into caudate putamen was assessed. A dose–response study with adenoviral vector-mediated vascular endothelial growth factor and a time course study at both 24 and 48 hours postinjection were performed. Effects of minocycline, a nonspecific MMP inhibitor, and pyrrolidine dithiocarbamate, an upstream regulator of MMPs, on MMP-9 activity and thereby the degree of ICH were also tested. Results—Adenoviral vector-mediated vascular endothelial growth factor at the higher dose and at 48 hours induced MMP-9 levels 6-fold (n=6, P=0.02) and increased brain tissue hemoglobin (43.4±11.5 versus 30.3±4.1 µg/mg, n=6, P=0.003) compared with the adenoviral vector control. Immnunostaining was positive for MMP-9 around the cerebral vessels and the hemorrhagic areas. Minocycline and pyrrolidine dithiocarbamate administration suppressed vascular endothelial growth factor-induced MMP-9 activity (n=6, P=0.003 and P=0.01, respectively) and the associated increases in hemoglobin levels (n=5–6, P=0.001 and P=0.02, respectively). Conclusions—Vascular endothelial growth factor-induced ICH is associated with increased MMP-9 expression. Suppression of MMP-9 by minocycline or pyrrolidine dithiocarbamate attenuated ICH, suggesting the therapeutic potential of MMP inhibitors in cerebral vascular rupture.
Revised on February 26, 2007
Accepted on March 15, 2007
Matrix Metalloproteinase-9 Inhibition Attenuates Vascular Endothelial Growth Factor-Induced Intracerebral Hemorrhage
Chanhung Z. Lee MD, PhD;
Key words: intracerebral hemorrhage • matrix metalloproteinase • minocycline • pyrrolidine dithiocarbamate • vascular endothelial growth factor
This article has been cited by other articles:
 |
|
 |
|
  C. Z. Lee, Z. Xue, Q. Hao, G.-Y. Yang, and W. L. Young Nitric Oxide in Vascular Endothelial Growth Factor-Induced Focal Angiogenesis and Matrix Metalloproteinase-9 Activity in the Mouse Brain Stroke, August 1, 2009; 40(8): 2879 - 2881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kim, L. Pawlikowska, Y. Chen, H. Su, G.-Y. Yang, and W. L. Young Brain Arteriovenous Malformation Biology Relevant to Hemorrhage and Implication for Therapeutic Development Stroke, March 1, 2009; 40(3_suppl_1): S95 - S97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 P. A. Murphy, M. T. Y. Lam, X. Wu, T. N. Kim, S. M. Vartanian, A. W. Bollen, T. R. Carlson, and R. A. Wang Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice PNAS, August 5, 2008; 105(31): 10901 - 10906. [Abstract] [Full Text] [PDF]
|
|