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

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 mu g/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.