Prokineticin 1 mediates fetal‐maternal dialogue regulating endometrial leukemia inhibitory factor

Abstract

Implantation requires communication between a receptive endometrium and a healthy blastocyst. This maternal-embryonic crosstalk involves local mediators within the uterine microenvironment. We demonstrate that a secreted protein, prokineticin 1 (PROK1), is expressed in the receptive endometrium and during early pregnancy. PROK1 induces expression of leukemia inhibitory factor (LIF) in endometrial epithelial cells and first trimester decidua via a Gq-Ca2+-cSrc-mitogen-activated protein kinase kinase-mediated pathway. We show that human embryonic chorionic gonadotropin (hCG) induces sequential mRNA expression of PROK1 and LIF in an in vivo baboon model, in human endometrial epithelial cells, and in first-trimester decidua. We have used micro RNA constructs targeted to PROK1 to demonstrate that hCG-mediated LIF expression in the endometrium is dependent on prior induction of PROK1. Dual immunohistochemical analysis colocalized expression of the luteinizing hormone/chorionic gonadotropin receptor, PROK1, PROKR1, and LIF to the glandular epithelial cells of the first trimester decidual tissue. PROK1 enhances adhesion of trophoblast cells to fibronectin and laminin matrices, which are mediated predominantly via LIF induction. These data describe a novel signaling pathway mediating maternal-embryonic crosstalk, in which embryonic hCG via endometrial PROK1 may play a pivotal role in enhancing receptivity and maintaining early pregnancy.—Evans, J., Catalano, R. D., Brown, P., Sherwin, R., Critchley, H. O. D., Fazleabas, A. T., Jabbour, H. N. Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor.

Cotinine Exposure Increases Fallopian Tube PROKR1 Expression via Nicotinic AChRα-7

“…13 Furthermore, PROK1 was recently reported to enhance the adhesion of human trophoblast cells to extracellular matrix proteins. 15 This effect was shown to be mediated through PROK1 upregulation of LIF, suggesting that increased PROK1 activity may result in enhanced endometrial receptivity. PROKs are potent angiogenic factors.…”

“…10 The difficulty in studying implantation is that tissues are collected after an implantation event has occurred, making it hard to ascertain whether differences observed are the result of a predisposing factor or implantation itself. However, our previous findings, 10 together with the purported roles of PROK1 in intrauterine implantation, [13][14][15] led us to hypothesize that dysregulated PROKR1 expression might predispose the tubal environment to ectopic pregnancy.…”

Effects of EG-VEGF, VEGF and TGF-β1 on pregnancy outcome in patients undergoing IVF-ET treatment

“…EG-VEGF may support pregnancy through angiogenesis and VP regulation [5,25]. It has been reported that EG-VEGF is expressed in human periimplantation endometrium, which expression and receptor are elevated in human decidua during early pregnancy, and that EG-VEGF can mediate fetal-maternal dialogue by regulating hCG-mediated endometrial LIF expression [26,27].…”

Role of EG-VEGF in Human Placentation: Physiological and Pathological Implications

“…It has been demonstrated that EG-VEGF, but not PROK2, expression peaks during the midluteal window of implantation, with immunolocalization to endometrial glandular epithelium, stromal and endothelial cells, and myometrial vascular endothelium as well as smooth muscle (Evans et al, 2009,Ngan et al, 2006. In addition, it has been suggested that EG-VEGF could have a role in mediating the dysregulated vascular permeability that occur in ovarian hyperstimulation syndrome.…”