Abstract
Successful pregnancy establishment in mammals depends on proper embryo-maternal communication. Prokineticin 1 (PROK1) is a secretory protein that exerts pleiotropic functions in various tissues. Despite the studies that have primarily been performed with human cell lines and mice, the function of PROK1 in trophoblasts has still not been fully elucidated. Hence, the aim of this study was to establish the role of PROK1 in trophoblasts during implantation and placentation. Prokineticin 1 mRNA was elevated in porcine trophoblasts during implantation and the early placentation period. Furthermore, we reveal that PROK1–PROKR1 signaling induces the expression of genes involved in the regulation of angiogenesis, immunological response, trophoblast cell adhesion, invasion, and proliferation, as well as stimulating phosphorylation of MAPK and PTK2. Ingenuity Pathway Analysis identified the aforementioned and also other functions associated with PROK1-regulated genes/proteins, such as cell-to-cell contact, epithelial tissue differentiation, Ca2+ release, lipid synthesis, and chemotaxis. We also showed evidence that PROK1 acting via PROKR1 increased trophoblast cell proliferation and adhesion. The PROK1-stimulated cell proliferation was mediated by PI3K/AKT/mTOR, MAPK, and cAMP, whereas adhesion was mediated by MAPK and/or PI3K/AKT signaling pathways. Concluding, our study suggests that PROK1 plays a pleiotropic role in trophoblast function during implantation and early placentation.
Highlights
Successful pregnancy establishment in mammals depends on proper embryo-maternal communication
We found that 24 h-treatment with Prokineticin 1 (PROK1) stimulated the trophoblast expression of genes involved in angiogenesis: ANGPT1, fms-related receptor tyrosine kinase 1 (FLT1) and kinase insert domain receptor (KDR) on day 15 of pregnancy (P < 0.05; Fig. 3A,F,G, respectively) and ANGPT2, communication network factor 2 (CCN2), cadherin 13 (CDH13), fibroblast growth factor 2 (FGF2), nuclear factor of activated T cells 2 (NFATC2), regulator of calcineurin 1 (RCAN1), and vascular endothelial growth factor A (VEGFA) (P < 0.05; Fig. 3B–E, and H–J, respectively) on days 15 and 20 of pregnancy
The upregulation of PROK1 mRNA abundance in porcine trophoblasts during implantation and the early placentation period corresponds with an increased expression of PROK1 and its receptor in the e ndometrium[7], which implies that PROK1 may be an important factor during conceptus development and pregnancy establishment
Summary
Successful pregnancy establishment in mammals depends on proper embryo-maternal communication. The maternal recognition of pregnancy, which in pigs is initiated on days 11–12 of pregnancy, is a process during which the conceptuses (embryos with associated membranes) signal their presence to the maternal system and prolong the lifespan of the corpus luteum (CL)[1] At this time, porcine conceptuses secrete increased levels of estrogens (including estradiol-17β; one of the major porcine conceptus signals for the establishment of pregnancy) and undergo elongation from spherical forms to tubular forms and to filamentous forms[2]. Recent findings indicate that prokineticin 1 (PROK1) may serve as a novel angiogenic factor involved in the regulation of implantation and p lacentation[7,8,9] This molecule ( called endocrine gland-derived VEGF) is a 11-kDa protein and its expression in humans has been reported, among others in the endometrium, placenta, trophoblast, ovary and fallopian tube[10]. Impaired PROK1 signaling has been linked with placental pathologies such as preeclampsia and intrauterine growth r estriction[12]
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