Title

Doxycycline suppresses cerebral matrix metalloproteinase-9 and angiogenesis induced by focal hyperstimulation of vascular endothelial growth factor in a mouse model

Document Type

Article

Abstract

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.

Keywords

Angiogenesis, Drug therapy, Metalloproteinases

Publication Date

7-1-2004

Publication Title

Stroke

ISSN

00392499

Volume

35

Issue

7

First Page

1715

Last Page

1719

PubMed ID

15166398

Digital Object Identifier (DOI)

10.1161/01.STR.0000129334.05181.b6

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