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bioRxiv · 10.1101/2022.11.22.517326

MMP2 loss leads to defective parturition and severe dystocia in mice

Kalev-Altman, R.·Levy, T.·Shpigel, N. Y.·Monsonego-Ornan, E.·Sela-Donenfeld, D.
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Abstract

Parturition is the final step of mammalian reproduction and an essential process for the species survival. During pregnancy, the uterus is maintained quiescence which is important for fetal growth and development. However, at term, fundamental changes in myometrial contractility are initiated for efficient expulsion of the fetus. These changes involve tissue remodeling that requires changes in the extracellular matrix (ECM). The gelatinases subgroup of matrix metalloproteinases (MMPs), has only two members: MMP2 and MMP9, which are both known to participate in uterine ECM remodeling throughout the estrus cycle as well as during pregnancy, parturition and postpartum involution. Yet, no knowledge exists regarding their loss-of-function impact on the uterus. Here we investigated the effect of MMP2 and/or MMP9 genetic loss on parturition process. Single and double knockout (dKO) mice for MMP2 and/or MMP9 were used. We found high percentages of dystocia in mmp2-/-, mmp2-/-mmp9+/- and dKO females, but not in mmp9-/- females. Histological analysis of nulliparous uterine tissue of WT, mmp2-/-, mmp9-/- and dKO, at 8 weeks, 4 months and 8-9.5 months, revealed that the uterine tissue of mmp2-/- presents alterations in tissue size and structure, mainly when reaching to 8-9.5 months of age, including enlarged total tissue, myometrium, endometrium and luminal cavity. Additionally, Massons Trichrome staining suggested a mechanism of extensive fibrosis in mmp2-/- myometrium, which may lead to dystocia. Altogether, our research highlights a novel cause for dystocia pathology mediated by loss of MMP2 activity in uterine tissue during mammalian parturition.

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Kalev-Altman, R., Levy, T., Shpigel, N. Y., Monsonego-Ornan, E., Sela-Donenfeld, D.. 2022-11-22. MMP2 loss leads to defective parturition and severe dystocia in mice. https://doi.org/10.1101/2022.11.22.517326

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