Spiral artery (SA) remodeling is a fundamental process during early pregnancy that involves the action of vascular smooth muscle cells (VSMCs), maternal immune cells, but also fetal extravillous trophoblast cells (EVTs) and the extracellular matrix (ECM). Mast cells (MCs) and their mediator chymase, have been identified as prominent players for a sufficient SA remodeling process at the fetal-maternal interface in vivo. In contrast, endocrine disrupting chemicals (EDC), especially Bisphenol A (BPA) and 17-α-ethinylestradiol (EE2), have been shown to have a negative impact on SA remodeling in animal models in vivo. However, neither the mechanisms underlying the positive effects of MCs and chymases for the remodeling process, nor the interference of EDCs on SA remodeling, have been elucidated. The purpose of the present work was to evaluate the effect of MCs and recombinant human chymase CMA1 (rhuCMA1) on the phenotype and/or behavior of VSMCs, EVTs and ECM in vitro. Moreover, the influence of BPA and EE2 on the functionality of EVTs in vitro was observed.
Using an immortalized human trophoblast cell line (HTR8/SV-neo), a mouse trophoblast cell line (SM9-2), human primary uterine vascular smooth muscle cells (HUtSMCs) and mouse primary uterine smooth muscle cells (SMCs), we assessed the effects of the human MC cell line HMC-1, the mouse mast cell line MC/9 and rhuCMA1 on VSMCs, EVTs and ECM. Additionally, the HTR- 8/SV-neo cells functionality was evaluated after treatment with BPA or EE2.
We found that mouse MC/9 cells induce fibronectin expression and migration in SMCs. Furthermore MC/9 cells increase the proliferation and migration of SM9-2 cells. Both human HMC-1 cells and rhuCMA1 stimulate the migration, proliferation, and change of
synthetic/contractile marker expression in HUtSMCs. In addition, HMC-1 cells increase the proliferation and migration of HTR8/SVneo trophoblast cells while having an impact on the expression of tissue remodeling genes. HTR8/SVneo cells presented increased migration rates along with decreased expression of the matrix-metalloproteinase regulator genes (TIMPs) upon treatment with rhuCMA1. Moreover, BPA interfered with HTR-8/SV-neo cell proliferation and reduced MMP2 expression in HTR-8/SV-neo. Interestingly, EE2 had no impact on proliferation or migration but suppressed the MMP2 expression in HTR-8/SV-neo cells.
The obtained results indicate that MCs, and partly their mediator chymase CMA1, shape the phenotype and modulate the functionality of VSMCs and EVTs. Collectively, possible mechanisms by which MCs and specifically rhuCMA1 promote SA remodeling were identified. The findings are relevant for the understanding of this crucial step in pregnancy and thus, for the comprehension of dysregulated pathways that can lead to pregnancy complications like fetal growth restriction and preeclampsia. Moreover, this work contributes to the knowledge about how EDCs impact on early pregnancy and highlights the high risk of EDCs exposure disturbing the fundamental reproductive process of SA remodeling.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84647 |
| Date | 11 April 2023 |
| Creators | Zhang, Ningjuan |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 10.3390/cells11071158 |
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