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(Stroke. 2004;35:1715.)
© 2004 American Heart Association, Inc.

Original Contributions

Doxycycline Suppresses Cerebral Matrix Metalloproteinase-9 and Angiogenesis Induced by Focal Hyperstimulation of Vascular Endothelial Growth Factor in a Mouse Model

Chanhung Z. Lee, MD, PhD; Bin Xu, MD; Tomoki Hashimoto, MD; Charles E. McCulloch, PhD; Guo-Yuan Yang, MD, PhD William L. Young, MD

From the Departments of Anesthesia and Perioperative Care (C.Z.L., B.X., T.H., G.-Y.Y., W.L.Y.), Epidemiology and Biostatistics (C.E.M.), Neurological Surgery (G.-Y.Y., W.L.Y.), and Neurology (W.L.Y.), and the Center for Cerebrovascular Research (C.Z.L., B.X., T.H., G.-Y.Y., W.L.Y.), University of California, San Francisco.

Correspondence to Dr William L. Young, Center for Cerebrovascular Research, 1001 Potrero Ave, Room 3C-38, San Francisco, CA 94110. E-mail ccr{at}anesthesia.ucsf.edu

Background and Purpose— 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.

Key Words: drug therapy • metalloproteinases • angiogenesis

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