Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Majali Martinez, A.
The role of placental matrix metalloproteinases 14 and 15 in inflammation-associated pregnancy diseases
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 92
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Desoye Gernot
- Dieber-Rotheneder Martina
- Altmetrics:
- Abstract:
- During the first trimester of pregnancy trophoblast cells invade the uterine wall and remodel the spiral arteries, allowing an adequate blood supply to the fetus. Shallow trophoblast invasion is associated with pregnancy complications such as preeclampsia (PE). Other PE hallmarks are endothelin-1 (ET-1) up-regulation, inflammation and hypoxia. Moreover, the risk for developing PE is increased in other pro-inflammatory conditions such as maternal obesity. Trophoblast invasion is determined by matrix metalloproteinases (MMPs). Two members of this protease family, MMP14 and MMP15, have been identified in first trimester trophoblasts, but the actual role of MMP15 still remains unknown. Hence, we hypothesized that MMP15 is key player for first trimester placental function, and that MMP14 and MMP15 are regulated by the PE stimuli mentioned above as well as by maternal obesity. For this purpose, MMP15 localization and function were investigated using immunofluorescence and human first trimester chorionic placental villi explants, respectively. Isolated first trimester trophoblasts were incubated with ET-1 (10nM or 100nM), tumor necrosis factor (TNF)-a (25ng/ml) or exposed to different oxygen tensions (1%, 2.5% and 20% O2). Then, MMP14 and MMP15 expression and protein levels were measured by RT-qPCR and Western blotting, respectively. ET-1 functional consequences were determined using chorionic villi explants and transwell invasion assays. Finally, MMP14 and MMP15 expression and protein levels were also measured in placental tissue from lean and obese pregnant women. The key findings of the study were: i) MMP15 is exclusively localized to invasive trophoblasts and is involved in trophoblast invasion; ii) ET-1 decreases MMP14 and MMP15 expression and protein levels in human first trimester trophoblasts and hinders trophoblast invasion; iii) TNF-a enhances ET-1-mediated MMP15 down-regulation; iv) low oxygen tension (1% O2) abolished the effect of ET-1 on MMP14 and MMP15 downregulation; v) maternal obesity correlated with an upregulation of MMP14 and a downregulation of MMP15 protein levels. In conclusion, MMP15 is crucial for trophoblast invasion. Together with MMP14, MMP15 needs to be tightly regulated for an adequate placental function. Alterations in the first trimester placental milieu toward a pro-inflammatory environment lead to MMP14 and MMP15 dysregulation, resulting in impaired trophoblast invasion, and might, therefore, be one of the causes underlying pregnancy complications such as PE.