© 1995 American Heart Association, Inc.
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In Situ Localization and Quantification of mRNA for 92-kD Type IV Collagenase and Its Inhibitor in Aneurysmal, Occlusive, and Normal Aorta
From the Division of Vascular Surgery, Department of Surgery, Department of Pathology and Medicine (B.K.P.), and the Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Ill.
Correspondence to William D. McMillan, MD, 251 E Chicago Ave, Suite 628, Chicago, IL 60611.
Abstract Ninety-two-kilodalton type IV
collagenase (MMP-9) is present in aortic
aneurysms and may be important to the pathogenesis of this
disease. Alteration in expression of MMP-9 or its
inhibitor, the tissue inhibitor of
metalloproteinase type 1 (TIMP-1), could increase degradation of
extracellular matrix and lead to aneurysm formation. The
purpose of this study was (1) to measure tissue levels of MMP-9 and
TIMP-1 mRNA in aneurysmal (AAA), atherosclerotic occlusive
(AOD), and normal (NL) human infrarenal aorta; (2) to test for their
expression by cultured AAA and NL vascular smooth muscle cells (VSMCs);
and (3) to locate in situ the cells responsible for mRNA
production within AAA, AOD, and NL aortic wall. Total RNA
extracted from AAA (n=8), AOD (n=8), and NL (n=7) tissue was subjected
to Northern analysis. Signals for MMP-9 and TIMP-1 were
normalized to 
-tubulin. Mean values±SEM were compared by ANOVA. NL
and AAA VSMCs were cultured, passaged, and grown to confluence before
RNA extraction and Northern analysis. In situ hybridization
with digoxigenin-labeled RNA probes localized cells responsible for
MMP-9 and TIMP-1 mRNA expression within sections of AAA (n=5), AOD
(n=2), and NL (n=2) aorta. MMP-9 mRNA levels were significantly greater
in AAA (0.855±0.180) than NL (0.046±0.23) (P<.02), but
differences between AOD (0.406±0.196) and AAA or AOD and NL were not
significant. Differences in TIMP-1 mRNA levels between tissue types
were not significant (AAA, 1.17±0.123; AOD, 1.79±0.351; NL,
0.652±0.378). Cultured AAA and NL aortic VSMCs constitutively
expressed mRNA for TIMP-1 but not MMP-9. In situ hybridization of AAA
and AOD tissue localized MMP-9 mRNA to adventitial macrophages
in areas of neovascularization and TIMP-1 mRNA to adventitial VSMCs.
MMP-9 mRNA levels are significantly greater in aneurysmal than
normal aorta. Cultured VSMCs constitutively express TIMP-1 but not
MMP-9. In the diseased aortic wall, MMP-9 mRNA is found in adventitial
macrophages and TIMP-1 mRNA in adventitial VSMCs. Localization
of MMP-9 mRNA expression to discrete areas surrounding vasa vasorum
suggests that the enzyme is responsible for localized matrix
alterations associated with neovascularization.
Key Words: aortic aneurysm • metalloproteinase • vasorum • TIMP
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