1. Aspirin alleviates fibronectin-induced preeclampsia phenotypes in a mouse model and reverses fibronectin-mediated trophoblast invasiveness under hypoxia by regulating ciliogenesis and Akt and MAPK signaling.
- Author
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Tsai PY, Lee CI, Tam HL, and Su MT
- Subjects
- Animals, Female, Pregnancy, Mice, Humans, Disease Models, Animal, Cilia drug effects, Cilia metabolism, Cilia physiology, Phenotype, Cell Hypoxia drug effects, Cell Hypoxia physiology, Hypoxia metabolism, Cell Line, Pre-Eclampsia metabolism, Pre-Eclampsia prevention & control, Pre-Eclampsia pathology, Fibronectins metabolism, Fibronectins genetics, Aspirin pharmacology, Trophoblasts drug effects, Trophoblasts metabolism, Mice, Inbred C57BL, Proto-Oncogene Proteins c-akt metabolism, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System physiology
- Abstract
The placenta experiences a low-oxygen stage during early pregnancy. Aspirin is an effective preventative treatment for preeclampsia if applied early in pregnancy. Elevation of fibronectin (FN) level has been reported to be associated with preeclampsia; however, the role of FN in the physiological hypoxic phase and whether aspirin exerts its effect on FN at this hypoxic stage remain unknown. We determined pregnancy outcomes by injecting saline or recombinant FN protein into C57BL/6 pregnant mice and one group of FN-injected mice was fed aspirin. The effects of FN, the underlying pathways on trophoblast biology, and cilia formation under hypoxia were investigated in FN-pretreated or FN-knockdown HTR-8/SVneo cells in a hypoxic chamber (0.1 % O
2 ). Preeclampsia-like phenotypes, including blood pressure elevation and proteinuria, developed in FN-injected pregnant mice. The fetal weight of FN-injected mice was significantly lower than that of non-FN-injected mice (p < 0.005). Trophoblast FN expression was upregulated under hypoxia, which could be suppressed by aspirin treatment. FN inhibited trophoblast invasion and migration under hypoxia, and this inhibitory effect occurred through downregulating ZEB1/2, MMP 9 and the Akt and MAPK signaling pathways. Ciliogenesis of trophoblasts was stimulated under hypoxia but was inhibited by FN treatment. Aspirin was shown to reverse the FN-mediated inhibitory effect on trophoblast invasion/migration and ciliogenesis. In conclusion, FN overexpression induces preeclampsia-like symptoms and impairs fetal growth in mice. Aspirin may exert its suppressive effect on FN upregulation and FN-mediated cell function in the hypoxic stage of pregnancy and therefore provides a preventative effect on preeclampsia development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)- Published
- 2024
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