Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracerebral hemorrhage

• Published in: Stroke (1970) 2007-09, Vol.38 (9), p.2563-2568
• Main Authors: LEE, Chanhung Z, ZHENG XUE, YIQIAN ZHU, YANG, Guo-Yuan, YOUNG, William L
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Animals; Anti-Bacterial Agents - metabolism; Antioxidants - metabolism; Biological and medical sciences; Brain - anatomy & histology; Brain - pathology; Brain - physiology; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cerebral Hemorrhage - chemically induced; Disease Models, Animal; Drug toxicity and drugs side effects treatment; Fundamental and applied biological sciences. Psychology; Humans; Intracranial Arteriovenous Malformations - metabolism; Male; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors; Medical sciences; Mice; Minocycline - metabolism; Neurology; Pharmacology. Drug treatments; Pyrrolidines - metabolism; Thiocarbamates - metabolism; Toxicity: nervous system and muscle; Vascular diseases and vascular malformations of the nervous system; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vertebrates: nervous system and sense organs
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.106.481515

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. 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. 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 mug/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). 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.