Gestational profile of matrix metalloproteinases in rat uterine artery.

Mechanisms underlying structural reorganization of the uterine artery in pregnancy remain largely unknown. Matrix metalloproteinases (MMPs) which are involved in degradation of vascular wall matrix are likely to play a key role. In this investigation of rat uterine artery, key MMPs and the specific tissue inhibitors of MMPs (TIMPs) together with three housekeeping genes were studied before, during and after pregnancy, using real time PCR. Data were analysed by partial least squares analysis as well as by conventional univariate methods. Each gene studied [MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, MMP-13, membrane-type 1 (MT1)-MMP, TIMP-1, TIMP-2, GAPDH, cyclophilin and beta-actin] increased in late pregnancy (day 21). MMP-2, MT1MMP, MMP-3 and TIMP-1 transcripts were also elevated at day 7. TIMP-1 and MMP-3 mRNA expression returned to virgin control values in the post-partum, whereas others remained elevated or increased further (MMP-9, MMP-13). Gelatin zymography showed maximum elevation of MMP-2 at day 21. A novel 43-45 kDa gelatinolytic doublet was observed which increased in density with gestation and may represent an active MMP-2 fragment. Together, these data strongly suggest that MMPs and TIMPs are likely to play an important role in remodelling uterine arteries in rat pregnancy and may represent means by which vasodilatation is maintained in later pregnancy. Continued elevated levels of some MMPs post-partum may contribute to vessel regression and return to a non-pregnant physiological state.