This study found that deletion of MMP-9 in aging mice (15-18 months old) improves cardiac function by enhancing angiogenesis and vascular permeability. Specifically, MMP-9 deletion was found to increase blood vessel growth and vascular endothelial growth factor levels in the left ventricle, as well as plasma levels of factors associated with angiogenesis. It also attenuated the age-related increase in vascular permeability and expression of genes related to both pro- and anti-angiogenic processes. The results suggest that MMP-9 contributes to reduced responses to pro-angiogenic stimuli, increased inflammation, and vascular permeability as mice age, before left ventricular dysfunction occurs.

1. MMP-9 deletion improves vascular permeability and angiogenesis in aging mice
Andriy Yabluchanskiy1,2, Yonggang Ma1,2, Ying Ann Chiao3, Andrew Voorhees1,4, Hai-Chao Han1,4,
Yu-Fang Jin1,5, and Merry L. Lindsey1,2,6
1San Antonio Cardiovascular Proteomics Center, 2Mississippi Center for Heart Research, UMMC, 3Department of Pathology, UWS,
4Department of Mechanical Engineering, UTSA, 5Department of Electrical and Computer Engineering, UTSA, and 6Research Service, G.V.
(Sonny) Montgomery VA Medical Center
• Aging is a major risk factor for cardiac morbidity and mortality;
• Increasing age associates with increased MMP-9 expression, increased
ECM deposition, and a decline in cardiac function;
• MMP-9 deletion attenuates diastolic dysfunction in mice over 18 months
of age.
INTRODUCTION
HYPOTHESIS
Initiating changes that lead to diastolic dysfunction in aged mice occur
before 18 months of age and are MMP-9 dependent.
EXPERIMENTAL DESIGN
RESULTS
Figure 1. WT and Null 15-18 mo adult mice have higher myocyte cross-sectional
areas compared to young controls, indicating hypertrophy of the
individual myocytes. An increase in myocyte size would generate a need for
additional blood vessels to supply the increase in oxygen demand.
Figure 5. MMP-9 deletion
increased VEGF protein
expression with age, suggesting
that Null 15-18 mo mice have
more pronounced angiogenic
stimuli in the left ventricles.
SUMMARY
Figure 4. MMP-9 deletion
increased the number of
blood vessels in the LV with
age. This result suggests
that Null 15-18 mo mice have
enhanced angiogenesis.
Figure 7. Aging increased left ventricular vascular permeability,
which was attenuated by MMP-9 deletion. These data suggest
that MMP-9 deletion prevents the age-associated increase in
vascular permeability.
ACKNOWLEDGEMENTS
This study was supported by National Institutes of Health (NIH) San Antonio
Cardiovascular Proteomics Center HHSN-268201000036C (N01-HV-00244),
HL075360, HL101430, HL095852, HL051971, and GM104357; and Biomedical
Laboratory Research and Development Service of the Veterans Affairs
Office of Research and Development Award 5I01BX000505
Figure 2. The increase
in Cdh1 expression in
the WT indicates
altered vascular
integrity, while the
decrease in Itgav
indicates inhibited
angiogenesis.
Figure 3. With age, MMP-9 deletion increased plasma levels of
stem cell factor, vascular cell adhesion molecule-1, and von
Willebrand factor. These factors are associated with increased
angiogenesis.
Figure 6. The increase in 5
genes CCR7, CCR10, IL-1f8,
IL-13, and IL-20 was
attenuated in the absence of
MMP-9. These genes exhibit
inflammatory, angiogenic (IL-
13 and IL-20), and anti-angiogenic
(CCR7 and
CCR10) properties. Our data
suggest that both pro- and
anti-angiogenic stimuli in the
aging myocardium are
attenuated by MMP-9
deletion.
CONCLUSION
• The age-associated increase in MMP-9 levels contributes to
desensitization of the cardiac tissue to pro-angiogenic
stimuli, and increased inflammation and vascular
permeability;
• These changes occur before the development of LV
dysfunction.
Inputs
• Group 1: Young C57BL/6J (WT)
6-9 months old (mo); n=12
• Group 2: Adult 15-18 mo WT
n=20
• Group 3: Young MMP-9 null (Null)
6-9 mo; n=12
• Group 4: Adult 15-18 mo Null
n=21
Output measurements
• Histology
• Real Time RT2-PCR
• Plasma proteomic profiling
• Immunoblotting
• Statistics: ANOVA with Student
Newman Keuls post-test, * p<0.05
vs respective 6-9 mo control, +
p<0.05 vs WT 15-18 mo.