Abstract
In mouse pregnancy, pubic symphysis (PS) remodels into an elastic interpubic ligament (IpL) in a temporally regulated process to provide safe delivery. It restores at postpartum to assure reproductive tract homeostasis. Recently, macrophage localization in the IpL and dynamic changes in the expression of inflammatory mediators observed from the end of pregnancy (D18, D19) to early days postpartum (1dpp, 3dpp) highlighted the necessity of the identification of the key molecules involved in innate immune processes in PS remodeling. Therefore, this study uses morphological and high-sensitivity molecular techniques to identify both macrophage association with extracellular matrix (ECM) remodeling and the immunological processes involved in PS changes from D18 to 3dpp. Results showed macrophage association with active gelatinases and ECM components and 25 differentially expressed genes (DEGs) related to macrophage activities in interpubic tissues from D18 to 3dpp. Additionally, microarray and proteomic analysis showed a significant association of interpubic tissue DEGs with complement system activation and differentially expressed proteins (DEPs) with phagocytosis, highlighting the involvement of macrophage-related activities in mouse PS remodeling. Therefore, the findings suggest that PS ECM remodeling is associated with evidence of macrophage modulation that ensures both IpL relaxation and fast PS recovery postpartum for first labor.
Highlights
In mouse pregnancy, pubic symphysis (PS) remodels into an elastic interpubic ligament (IpL) in a temporally regulated process to provide safe delivery
Double immunostaining assay showed that while only single F4/80+ cells were immunolocalized at D19 pseudocavity borders (Fig. 1H), double-positive F4/80+/VEGFR2+ cells were localized at 3dpp pseudo-cavities (Fig. 1I), indicating that two distinct F4/80+ cells populations might be involved in the pseudo-cavity organization at D19 and 3dpp
Considering that enzymatic activity at interpubic tissue remodeling leads to extracellular matrix (ECM) structural changes[8,16] and that some ECM components can modulate macrophage differentiation and the function of M mps[32], we investigated the co-localization between F4/80+ cells and hyaluronic acid (HA), versican, decorin or active gelatinases at the end of pregnancy and early postpartum
Summary
Pubic symphysis (PS) remodels into an elastic interpubic ligament (IpL) in a temporally regulated process to provide safe delivery. Pregnancy (D19) is due to the combined action of hormones and a wide variety of proteolytic enzymes, such as matrix metalloproteinases (Mmps), dipeptidyl peptidases (ADAMTs) and tissue inhibitor of metalloproteinases (Timps) and hyaluronidases (Hyals)[8,16] These molecules change the levels of proteoglycan, hyaluronic acid (HA), collagen, elastic fibers and water of IpL, leading to the increase in compliance and extendibility of this ligament before parturition[8,9,10,17]. Macrophages are involved in a wide range of gestational processes, including regulation of immune cell activities, placental cell invasion, initiation of labor and postpartum reproductive organ r emodeling[19,23,24,25,26,27,28,29] These cells show significant heterogeneity in function, majorly affected by their microenvironment. Aberrant modifications in the mouse reproductive tract or pelvic floor EMC molecules seem to be intimately associated with increased pro-inflammatory cytokine production in pelvic organs[34] and lead to exacerbated interpubic tissue relaxation for labor[15]
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