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.
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA 94110, USA.
Chanhung Z
CZ
Lee
Zheng
Z
Xue
Yiqian
Y
Zhu
Guo-Yuan
GY
Yang
William L
WL
Young
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