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


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.
Lee
Chanhung Z
CZ
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA 94110, USA.
Xue
Zheng
Z
Zhu
Yiqian
Y
Yang
Guo-Yuan
GY
Young
William L
WL
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D002543:Cerebral Hemorrhage / Q000139:chemically induced*; D004195:Disease Models, Animal; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008911:Minocycline / Q000378:metabolism; D011759:Pyrrolidines / Q000378:metabolism; D013859:Thiocarbamates / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D061965:Matrix Metalloproteinase Inhibitors; D011759:Pyrrolidines; D013859:Thiocarbamates; D042461:Vascular Endothelial Growth Factor A; C020972:pyrrolidine dithiocarbamic acid; D020780:Matrix Metalloproteinase 9; D008911:Minocycline