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    Cyclophilin A inhibits trophoblast migration and invasion in vitro and vivo through p38/ERK/JNK pathways and causes features of preeclampsia in mice. Hu Haoyue,Jiang Jiayi,Chen Qian,Wei Songren,Liu Mian,Chen Xia,Fan Cuixia,Ma Jing,Chen Wenqian,Wang Xuefei,Zhong Mei Life sciences AIMS:Numerous studies suggest that excessive maternal inflammation and defective extravillous trophoblast (EVT) invasion could contribute to the development of preeclampsia (PE), but the underlying mechanism remains unclear. Some evidence suggests that CyPA is elevated in PE. This research aims to investigate the effect of recombinant human CyPA on trophoblast migration and invasion both in vitro and in vivo. MATERIALS AND METHODS:We detected the expression and localization of CyPA in human placenta and explored the effects of CyPA on cell migration and invasion on HTR8/SVneo cell. Additionally, the expression levels of matrix metalloproteinase (MMP)-2/9 and molecules in the p38/ERK/JNK signaling pathway were detected. We established a mouse model by injecting pregnant mice with recombinant human CyPA and measured blood pressure, albumin/creatinine ratio, fetal and placenta weight of mice. Moreover, we examined the placental histology and MMP-2/9 and p38/ERK/JNK expression. KEY FINDINGS:Our results showed that CyPA inhibited the migration and invasion of HTR8/SVneo cells in a dose-dependent manner, decreasing the expression of matrix metalloproteinase (MMP)-2/9 and molecules in the p38/ERK/JNK signaling pathway. Silencing CyPA could reverse the above effects. Moreover, CyPA could induce PE-like features in pregnant mice and disrupt the structure of the mouse placenta by reducing the junctional zone area. CyPA attenuated the trophoblast invasiveness in mice placenta by downregulating MMP-2/9 expression and p38/ERK/JNK pathway activity. SIGNIFICANCE:We proposed that CyPA could inhibit trophoblast migration and invasion both in vitro and in vivo, which was involved in PE development. 10.1016/j.lfs.2020.118351
    Bone morphogenetic protein 2 promotes human trophoblast cell invasion and endothelial-like tube formation through ID1-mediated upregulation of IGF binding protein-3. Zhao Hong-Jin,Klausen Christian,Zhu Hua,Chang Hsun-Ming,Li Yan,Leung Peter C K FASEB journal : official publication of the Federation of American Societies for Experimental Biology Extravillous cytotrophoblasts (EVTs) invade into the uterine wall and remodel spiral arteries for proper placentation. Studies from us and others have demonstrated that the transforming growth factor-β superfamily member bone morphogenetic protein 2 (BMP2) plays important roles in endometrial decidualization and trophoblast cell invasion. However, BMP2 has also been shown to regulate endothelial cell migration and capillary-like tube formation, as has its downstream signaling molecule inhibitor of DNA binding 1 (ID1). Interestingly, insulin-like growth factor binding protein 3 (IGFBP3) also promotes cell migration and angiogenesis in endothelial precursor cell. Moreover, Id1 has a regulatory effect on Igfbp3 expression in rat prostate epithelial cells. However, whether ID1 and IGFBP3 are integrated in BMP2 signaling and involved in the regulation of trophoblast invasive and endovascular differentiation remains unknown. The objective of our study was to examine the effects of BMP2 on ID1 and IGFBP3 expression and their roles in BMP2-regulated human trophoblast invasion and endothelial-like tube formation. Primary and immortalized (HTR8/SVneo) cultures of human trophoblast cells were employed as study models. BMP2 treatment increased ID1 and IGFBP3 mRNA and protein levels in HTR8/SVneo and primary human EVT cells. Intriguingly, ID1 was essential for BMP2-induced IGFBP3 upregulation in both study models, and BMP2-induced trophoblast invasion was attenuated by knockdown of either ID1 or IGFBP3. In addition, BMP2 significantly increased endothelial-like tube formation and knockdown of ID1 and IGFBP3 reduced basal and BMP2-induced tube formation in HTR8/SVneo cells. Similarly, BMP2 increased placenta growth factor (PlGF) production in HTR8/SVneo cells and these effects were attenuated by knockdown of ID1 or IGFBP3. Our results reveal that BMP2 promotes trophoblast cell invasion and endothelial-like tube formation by ID1-mediated IGFBP3 upregulation. 10.1096/fj.201902168RR
    Delta-Like 4-Notch signaling regulates trophoblast migration and invasion by targeting EphrinB2. Luo Qingqing,Zhang Wen,Liu Xiaoxia,Zheng Yanfang,Gao Hui,Zhao Yin,Zou Li Biochemical and biophysical research communications The migration and invasion of trophoblasts during early pregnancy in known to play an important role in placental development, which ensures the oxygen and nutrients to the fetus. Accumulating evidences suggest that Delta-Like 4(DLL4)-Notch signaling may be involved in the process of trophoblast regulation. However, the potential role of DLL4-Notch signaling as well as its molecular mechanism in trophoblast controlling has not been fully studied. This study is designed to investigate the effects of DLL4-Notch signaling on trophoblast functions in human extravillous trophoblast cell line, HTR-8/SVneo. The possible molecular mechanism of DLL4-Notch signaling in trophoblast was also explored. We observed that activation of DLL4-Notch signaling enhanced cell migration and invasion ability while blockage of DLL4-Notch signaling impaired. Control of DLL4-Notch signaling did not affect cell viability. The expression of EphrinB2 was regulated by DLL4-Notch signaling. In addition, up-regulation of EphrinB2 resulted in the similar effects on trophoblast cell functions as DLL4-Notch signaling activation. Moreover, activation of DLL4-Notch signaling reversed the negative impact of EphrinB2 knock-down on trophoblasts migration and invasion. Our study suggested that DLL4-Notch signaling involved in the regulation of trophoblast migration and invasion, which may be induced by direct regulation of EphrinB2 expression. 10.1016/j.bbrc.2020.05.032