LIFR increases the release of soluble endoglin via the upregulation of MMP14 expression in preeclampsia

Abstract

Preeclampsia (PE) is a pregnancy-specific disorder that is the main cause of maternal and perinatal morbidity and mortality worldwide. Inadequate trophoblastic invasion and endothelial dysfunction in the placenta are considered the foundation of the pathogenesis of preeclampsia in which soluble endoglin (sENG) plays an antiangiogenic role in the development of PE. The leukemia inhibitory factor receptor (LIFR) has been widely studied and is highly involved in arterial injury and in the migration of cancer cells Here, we tested the hypothesis that LIFR may be correlated with preeclampsia through its regulation of the release of sENG. Our data showed that LIFR protein, the expression of which significantly decreased with the progression of pregnancy, was located in the syncytiotrophoblast and cytotrophoblast. The LIFR protein level was increased in pregnancies with preeclampsia compared with normotensive full-term pregnancies. After the overexpression of LIFR in HTR8/SVneo cells, the release of sENG as well as the migration and invasion were significantly enhanced. Moreover, we also observed that LIFR induced the expression of matrix metalloproteinase14 (MMP14) and that the knockdown or inhibition of MMP14 decreased the release of sENG, as well as increased the LIFR-induced migration and invasion of HTR8/SVneo cells. These studies demonstrated that LIFR promoted the release of sENG through MMP14 , which indicates that LIFR may be involved in the development of preeclampsia.

The diagnosis values of serum STAT4 and sEng in preeclampsia

“…Studies have shown that 65Da sEng monomer in the placenta of patients with preeclampsia is four times higher than normal pregnant patients . The mechanism by which sEng participates in the pathophysiological process of preeclampsia is not well understood . sEng is almost undetectable in non‐pregnant women.…”

“…31 The mechanism by which sEng participates in the pathophysiological process of preeclampsia is not well understood. 11,[32][33][34] sEng is…”

Unbiased placental secretome characterization identifies candidates for pregnancy complications

“…These included annexin A5 (ANXA5) an anticoagulant protein, inhibin beta A chain (INHBA), which is a subunit of both inhibin and activin, transthyretin (TTHY) a thyroid hormone-binding protein, insulin-degrading enzyme (IDE), which binds to insulin and leukaemia inhibitory factor receptor (LIFR). Whilst proteins like ANXA5, inhibins/activins, TTHY and LIFR have been previously reported to be secreted from the placenta 15,45–47 , we are not aware of any studies describing the secretion of other proteins, like IDE from the human placenta. Furthermore, other secreted proteins such as adipocyte enhancer-binding protein 1 (AEBP1) and Y-box-binding protein 1 (YBOX1), which can regulate transcription were also detected in the placental secretome.…”

“…Additionally, the placenta secretes inhibins, activins and relaxins, which aid in the adaptation of the endocrine, renal, circulatory and immune systems of the mother during gestation 13,14 . Finally, the placenta secretes proteases, inhibitors of peptidases, binding proteins and soluble forms of receptors for steroids, growth factors, cytokines and circulating factors, like lipoproteins, which contribute to the pleiotropic endocrine regulation of maternal physiology during gestation and show some predictive value for conditions like IUGR 15–18 . Thus, there is likely a constellation of protein mediators secreted by the placenta that facilitate maternal adaptations and ensure adequate fetal growth, required for a healthy pregnancy outcome.…”