Effects of tissue inhibitor of metalloproteinase 2 deficiency on aneurysm formation

Objective: 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. Methods: 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. Results: 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. Conclusions: 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.