Doxycycline suppresses cerebral matrix metalloproteinase-9 and angiogenesis induced by focal hyperstimulation of vascular endothelial growth factor in a mouse model.
OBJECTIVE
A number of central nervous system (CNS) disorders are associated with abnormalities in or activation of angiogenesis, including vascular malformations. To test the hypothesis that the nonspecific matrix metalloproteinase (MMP) inhibitor, doxycycline, suppresses vascular endothelial growth factor (VEGF)-induced cerebral angiogenesis through inhibition of MMPs, we used a mouse model with enhanced cerebral angiogenesis induced by focal hyperstimulation of VEGF from adenovirus DNA (AdVEGF) transduction.


METHODS
The time course study of MMP activity was performed at 7 and 14 days after AdVEGF transduction. MMP activity and expression were examined by zymography and immunohistochemistry, respectively. As an index of cerebral angiogenesis, microvessel counting was performed in the brains of 3 groups of mice (n=6): (1) control; (2) AdVEGF only; and (3) AdVEGF plus doxycycline (30 mg/kg per day).


RESULTS
Brain MMP-9 activities increased 4-fold (883+/-137 versus 179+/-179; 1-sided P<0.001) at 7 days after AdVEGF transduction. VEGF transduction increased vessel counts by 19% (255+/-27 versus 215+/-15, 1-sided P<0.01). Doxycycline treatment decreased MMP-9 activity (89+/-72 versus 883+/-137; 1-sided P<0.001) and cerebral microvessel number (231+/-17 versus 255+/-27; 1-sided P<0.05).


CONCLUSIONS
Doxycycline is effective in decreasing stimulated cerebral MMP-9 activity and parenchymal angiogenesis. The decrease in MMP-9 activity is associated with decreased microvessel counts. Brain pathophysiological processes that involve abnormally enhanced angiogenesis may be amenable to manipulation by MMP inhibitors, including tetracycline derivatives.
Lee
Chanhung Z
CZ
Department of Anesthesia and Perioperative Care, University of California, San Francisco, USA.
Xu
Bin
B
Hashimoto
Tomoki
T
McCulloch
Charles E
CE
Yang
Guo-Yuan
GY
Young
William L
WL
D000256:Adenoviridae; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000201:enzymology; D004318:Doxycycline / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D023421:Models, Animal; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline