Abstract
BackgroundTightly regulation of extravillous cytotrophoblast (EVT) cell invasion is critical for the placentation and establishment of a successful pregnancy. Insufficient EVT cell invasion leads to the development of preeclampsia (PE) which is a leading cause of maternal and perinatal mortality and morbidity. Transforming growth factor-beta1 (TGF-β1) and kisspeptin are expressed in the human placenta and have been shown to inhibit EVT cell invasion. Kisspeptin is a downstream target of TGF-β1 in human breast cancer cells. However, whether kisspeptin is regulated by TGF-β1 and mediates TGF-β1-suppressed human EVT cell invasion remains unclear.MethodsThe effect of TGF-β1 on kisspeptin expression and the underlying mechanisms were explored by a series of in vitro experiments in a human EVT cell line, HTR-8/SVneo, and primary cultures of human EVT cells. Serum levels of TGF-β1 and kisspeptin in patients with or without PE were measured by ELISA.ResultsTGF-β1 upregulates kisspeptin expression in HTR-8/SVneo cells and primary cultures of human EVT cells. Using pharmacological inhibitor and siRNA, we demonstrate that the stimulatory effect of TGF-β1 on kisspeptin expression is mediated via the ALK5 receptor. Treatment with TGF-β1 activates SMAD2/3 canonical pathways as well as ERK1/2 and PI3K/AKT non-canonical pathways. However, only inhibition of ERK1/2 activation attenuates the stimulatory effect of TGF-β1 on kisspeptin expression. In addition, siRNA-mediated knockdown of kisspeptin attenuated TGF-β1-suppressed EVT cell invasion. Moreover, we report that serum levels of TGF-β1 and kisspeptin are significantly upregulated in patients with PE.ConclusionsBy illustrating the potential physiological role of TGF-β1 in the regulation of kisspeptin expression, our results may serve to improve current strategies used to treat placental diseases.
Highlights
Regulation of extravillous cytotrophoblast (EVT) cell invasion is critical for the placentation and establishment of a successful pregnancy
The expression of kisspeptin is upregulated by TGF‐β1 in human EVT cells To examine the effect of Transforming growth factor-beta1 (TGF-β1) on kisspeptin expression in human EVT cells, HTR-8/SVneo human EVT cells were treated with 5 or 10 ng/mL TGF-β1 for 12 and 24 h
To avoid unknown off-target effects of pharmacological inhibitor and further confirm the requirement of the ALK5 in the TGF-β1-induced kisspeptin expression, ALK5 specific Small interfering RNA (siRNA) was applied to knockdown ALK5 expression
Summary
Regulation of extravillous cytotrophoblast (EVT) cell invasion is critical for the placentation and establishment of a successful pregnancy. Transforming growth factor-beta (TGFβ1) and kisspeptin are expressed in the human placenta and have been shown to inhibit EVT cell invasion. Placental development is marked by extravillous cytotrophoblast (EVT) cells invading the uterine wall and spiral arteries, replacing the cells of the vessel wall and creating a high-flow low-resistance vessel that ensures a continuous blood supply to the placenta throughout pregnancy. Insufficient human trophoblast cell invasion into the uterine decidua and inadequate remodeling of the uterine vasculature leads to the development of preeclampsia (PE) which is a serious complication of pregnancy defined by high blood pressure and proteinuria [3, 4]. Kisspeptin and GPR54 are highly expressed in the human placenta that plays important role in the regulation of placentation [8]. In the placenta of PE patients, the expression levels of kisspeptin are upregulated when compared to that in the placenta of uncomplicated pregnancies [13]
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