Role of TIMP-1 and TIMP-2 in the Progression of Cerebral Aneurysms

Abstract

The degradation of extracellular matrix (ECM) is a hallmark of a cerebral aneurysm; however, little is known regarding the molecular mechanism leading to this change. Tissue inhibitor of matrix metalloproteinase (TIMP) regulates the ECM degradation in vascular walls by inhibiting the activity of matrix metalloproteinases (MMPs). We investigated the role of TIMPs in the progression of cerebral aneurysms in the present study. TIMP-1 and TIMP-2 expression was examined by immunohistochemistry and quantitative RT-PCR in experimentally-induced cerebral aneurysms in rats. The incidence of aneurysmal changes in TIMP-1(-/-) and TIMP-2(-/-) mice was compared with that in the wild-type mice. TIMP-1 and TIMP-2 were expressed mainly by smooth muscle cells in aneurysmal walls. Quantitative PCR showed an increase of TIMP-1 and TIMP-2 mRNA in the early stage of aneurysm progression (form 0 to 1 month) but not in the late stage (form 1 to 3 months), whereas mRNA expression of MMP-2 and MMP-9 dramatically increased in the late stage. In both TIMP-1(-/-) mice and TIMP-2(-/-) mice, aneurysm progression was promoted with the increased enzyme activity of MMPs. Our findings suggest that TIMP-1 and TIMP-2 have a protective role for the progression of cerebral aneurysms. There is an imbalance between MMPs and TIMPs in the late stage of cerebral aneurysm formation, which may be responsible for ECM degradation leading to the progression and rupture of cerebral aneurysms.