Human Uterine Decidual NK Cells in Women with a History of Early Pregnancy Enhance Angiogenesis and Trophoblast Invasion

Abstract

Objective. The present study aimed to identify changes in decidual natural killer (dNK) cells and related cytokines in women who have undergone induced abortions (IAs). The effects of dNK cells on subsequent pregnancies remain unknown. Accordingly, we sought to investigate whether a history of early pregnancy can change dNK cells and facilitate their role in the regulation of angiogenesis and trophoblast invasion. Materials and Methods. dNK cells were obtained from primiparous women who had undergone IA(s) prior to this study and primiparous women who had never been pregnant before this IA (control). Real-time polymerase chain reaction (PCR) was used to measure the mRNA levels of IFN-γ, IP-10, VEGF, and PLGF in dNK cells. The levels of these cytokines were quantified using the enzyme-linked immunosorbent assay. HUVEC and HTR-8/SVneo cells were used to evaluate the angiogenesis, migration, and invasion activities influenced by dNK cells. Results. In dNK cells, the mRNA level of IFN-γ was higher in the control group than that in the IA group. The secretion of IP-10 and VEGF was higher in the IA group compared to the control group. After coculturing with the dNK supernatant, the HTR-8/SVneo cells exhibited better invasiveness and migration in the IA group than those in the control group. Angiogenesis assay demonstrated that dNK cells from IA group might help HUVEC attain better tube formation ability. Conclusion. The findings of this study suggest that a history of early pregnancy has an impact on dNK cells. These trained dNK cells can regulate angiogenesis and trophoblast invasion and migration by promoting the production of certain cytokines.

Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors—A Preliminary Study

“…Several studies demonstrated that dNK cells produced angiogenic factors and cytokines such as PIGF, IL-8, IFN-γ, Ang I, Ang II, which influenced endothelial integrity, and the imbalanced expression resulted in endothelial barrier dysfunction and vascular permeability in RPL patients [ 18 , 27 , 57 ]. In 2016, Cavalli et al showed that idNK cells obtained from pbNK cells by culturing in transformation media in hypoxia expressed similar factors [ 24 ].…”

“…A total of 70% of the decidual immune cells as so-called ‘decidual NK cells (dNK)’ [ 25 ] have a high capacity of producing cytokines such as IFN-γ, TNF-α, GM-CSF, TGF-β, and IL-10. Previous reports implied that this special population of dNK cells was involved in decidualization, angiogenesis [ 24 ], the regulation of trophoblast invasion [ 18 ], and spiral artery remodeling [ 26 ] by promoting the production of certain cytokines and factors, e.g., interferon gamma-induced protein 10 (IP-10), vascular endothelial growth factor A (VEGF-A), and IFN-γ [ 27 ]. The expression of placental growth factor (PIGF), angiogenin, endostatin, and sIL-2R increased by dNK cells may contribute to pregnancy disorders associated with poor spiral artery remodeling [ 25 ].…”

Angiogenic Properties of NK Cells in Cancer and Other Angiogenesis-Dependent Diseases

“…During the course of pregnancy, dNK cells support decidual vascularization and the development of spiral arteries, which enhances the nutritional role of the placenta. The strong proangiogenic effect of dNK cells is manifested by the secretion of many proangiogenic cytokines and chemokines, such as VEGF, IL-8, angiogenin, Ang-2, stromal-derived factor-1 (SDF-1/CXCL12), IFN-γ, as well as matrix metalloproteinase (MMP)9 and MMP2 [ 6 , 9 , 55 , 58 , 71 ]. It is particularly metalloproteinases that stimulate angiogenesis and trophoblast invasion through extracellular matrix (ECM) remodeling [ 72 ].…”

Decreased Production of TNF-α and IL-6 Inflammatory Cytokines in Non-Pregnant Idiopathic RPL Women Immunomodulatory Effect of Sildenafil Citrate on the Cellular Response of Idiopathic RPL Women

“…A high level of cGMP results in increased NO production, and consequently causes the relaxation of vascular smooth muscles, increases vasodilation and modulates immune response [ 15 , 16 ]. Therefore, sildenafil citrate is currently applied for the treatment of such intragestational complications as intrauterine growth restriction (IUGR) [ 6 , 17 , 18 , 19 ], low birth weight [ 5 ], preeclampsia or idiopathic recurrent pregnancy loss (RPL) [ 5 , 7 , 19 , 20 , 21 , 22 ]. Some experiments conducted on animal models, where SC was orally administered, suggested that SC might decrease IL-1, and TNF-α in the placenta of pregnant mice [ 23 , 24 ].…”