Abdominal aortic aneurysms (AAA) result from a degenerative process involving the destruction of the extracellular matrix (ECM) that leads to arterial wall weakening, dilatation, and eventual rupture. There is compelling evidence showing that enlargement of AAA is associated with monocyte/macrophage infiltration, ECM remodeling, neovascularization of the adventitia, and cellular death. The etiology of aortic aneurysms is unknown, but is probably multifactorial involving an initiating event (injury), a genetic predisposition, and an impaired wound healing response. The long-term goal of our research is to understand the pathogenesis of abdominal aortic aneurysms. Preliminary studies have suggested a correlation with between increased matrix metalloproteinase-9 (MMP-9) mRNA and plasma levels and aneurysms. Based on these studies we hypothesize that the arterial repair mechanisms in patients with AAA are abnormal with excessive matrix destruction resulting from over-expression of MMP-9 (gelatinase-b). The experiments described in this proposal will directly test the hypothesis that aberrant vascular remodeling plays an important role in aneurysm formation and may result in a model system that allows detailed characterization of the pathogenesis of aneurysms. We propose to develop and characterize a transgenic mouse model that over-expresses MMP-9 specifically in vascular smooth muscle. In parallel we propose to expand our clinical evaluation of plasma MMP-9 levels in aneurysm patients as compared to an age and sex-matched control group of patients with aortic occlusive disease. We will establish optimal sensitivity and specificity values for plasma MMP-9 levels using ROC analysis and multiple logistic regression. Plasma MMP-9 levels will be followed in a subgroup of patients longitudinally to predict rapid expansion. Additionally, plasma MMP-9 levels will be followed after open and endovascular repair.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064326-04
Application #
6527321
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Program Officer
Wassef, Momtaz K
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$367,500
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611