Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways

Abstract

Prostaglandin F2a (PGF2A) has multiple roles in the birth process in addition to its vital contractile role. Our previous study has demonstrated that PGF2A can modulate uterine activation proteins (UAPs) in cultured pregnant human myometrial smooth muscle cells (HMSMCs). The objective of this study was to define the signalling pathways responsible for PGF2A modulation of UAPs in myometrium. It was found that PGF2A stimulated the expression of (GJA1) connexin 43 (CX43), prostaglandin endoperoxide synthase 2 (PTGS2) and oxytocin receptor (OTR) in cultured HMSMCs. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked PGF2A-stimulated expression of CX43. The inhibitors of ERK, P38 and NFkB also blocked the effect of PGF2A on CX43 expression, whereas PI3K and calcineurin/nuclear factor of activated T-cells (NFAT) pathway inhibitors did not reverse the effect of PGF2A on CX43. For PTGS2 and OTR, PLC, PI3K, P38 and calcineurin/NFAT signalling pathways were involved in PGF2A action, whereas PKC and NFkB signalling were not involved. In addition, PGF2A activated NFAT, PI3K, NFkB, ERK and P38 signalling pathways. Our data suggest that PGF2A stimulates CX43, PTGS2 and OTR through divergent signalling pathways.

Systematic review of p38 mitogen‐activated kinase and its functional role in reproductive tissues

“…Kim et al reported that the oxytocin‐oxytocin receptor complex activates p38 MAPK and induces COX‐2 and IL‐8 in myocytes. Xu et al validated these findings, showing PGF2α production mediated by p38 MAPK through the same mechanism. A new oxytocin receptor antagonist, nolasiban, was shown to inhibit NF‐κB and p38 MAPK signaling, downregulating cytokine production in myometrial cells .…”

“…A new oxytocin receptor antagonist, nolasiban, was shown to inhibit NF‐κB and p38 MAPK signaling, downregulating cytokine production in myometrial cells . Along with oxytocin, reports documented p38 MAPK activation by proinflammatory mediators that stimulates myometrial activation . Specifically, IL‐1β and interferons have been documented as activators of p38 MAPK in myometrial cells, which induces prostaglandin synthesis and inflammation .…”

“…Specifically, IL‐1β and interferons have been documented as activators of p38 MAPK in myometrial cells, which induces prostaglandin synthesis and inflammation . Activation of these signaling pathways creates a feed‐forward loop, perpetuating proinflammatory cytokines and COX‐2 production associated with parturition …”

Estradiol Reduces Connexin43 Gap Junctions in the Uterus during Adenomyosis in Cows

“…All these studies reported an increase in Cx43 in the myometrium during term and preterm delivery as essential for the development of uterine contractions. Xu et al (2015) have showed lately that in human uterine myometrial cells prostaglandin F2alpha directly stimulated Cx43 protein expression. Thus, prostaglandins as main factors influencing on uterine function regulate Cx43 and this regulation may also differ during adenomyosis but it demands further study.…”

“…A gap junction channel is composed of two hemi-channels (connexons), each of which is composed of six protein subunits (connexins -Cxs) arranged around a pore. Connexin43 (Cx43) and Cx32 are the two most abundant Cxs and are expressed in numerous tissues including the ovary, placenta and decidua in several species, including cattle (Wiesen and Midgley 1993, Mayerhofer and Garfield 1995, Wrenzycki et al 1995, van Engelen et al 2009, Xu et al 2015.…”