Matrix metalloproteinase (MMP)-2 has been shown to play a pivotal role in aortic aneurysm formation. Its activation requires formation of a trimolecular complex of MMP-2, tissue inhibitor of metalloproteinase-2 (TIMP-2), and membrane type 1 (MT1)-MMP, which is attached to the cell surface. At higher concentrations, TIMP-2 becomes an inhibitor of MMP-2. Thus, TIMP-2 could both augment and inhibit matrix degradation. This study was undertaken to define the net effect of TIMP-2 on matrix destruction and aneurysm formation.The abdominal aortas of wild-type and TIMP-2-deficient (TIMP-2 -/-) mice were exposed to 0.25 mol/L CaCl2 or 0.9% NaCl for 15 minutes after laparotomy. Aortic diameters were measured before treatment and 6 weeks after aneurysm induction. In addition, aortic tissues were studied for MMP-2 activation by zymography, and matrix structure was studied by connective tissue staining.The aortic diameter increased in both wild-type and TIMP-2-/- mice. The increase in the TIMP-2 -/- mice was significantly smaller after CaCl2 treatment (51% +/- 3%) compared with the diameter of wild-type mice (67% +/- 4%). Connective staining of aortic sections from the CaCl2-treated mice revealed disruption and fragmentation of the medial elastic lamellae in both wild-type and TIMP-2 -/- mice. Zymographic analysis showed that active MMP-2 levels were decreased in TIMP-2 -/- aortas compared with wild-type mice.Targeted deletion of TIMP-2 results in attenuation of aneurysm development. Despite its name as an inhibitor of MMPs, TIMP-2 promotes aortic enlargement in vivo, presumably through its role as a cofactor in the activation of MMP-2.Abdominal aortic aneurysmal (AAA) disease is a potentially fatal disorder that screening studies have detected in 2% to 9% of the general population. Medical therapy designed to inhibit the progression of small aneurysms includes control of hypertension and smoking cessation; neither of these measures is of proven benefit. Effective and directed medical treatments for small AAAs await elucidation of key etiologic factors. Understanding precisely which molecules mediate AAA development, and blocking the activity of these molecules, could lead to important new therapies. Through our research, we have found that tissue inhibitor of metalloproteinase (TIMP)-2 has a role in this process in an experimental model of aortic aneurysms. We believe that TIMP-2 promotes aortic enlargement in vivo by activating matrix metalloproteinase 2.