BOR Papers in Press . Published on July 10 , 2013 as

Gap junctions play an important role in cell-to-cell communication, a process obviously required for embryo implantation. Uterine luminal epithelium (LE) is the first contact for an implanting embryo and is critical for the establishment of uterine receptivity. Microarray analysis of LE from periimplantation mouse uterus showed low level expression of 19 gap junction proteins in preimplantation LE and upregulation of gap junction protein, beta 2 (GJB2, connexin 26, Cx26) in postimplantation LE. Timecourse study using in situ hybridization and immunofluorescence revealed upregulation of GJB2 in the LE surrounding implantation site prior to decidualization. Similar dynamic expression of GJB2 was also observed in the LE of artificially decidualized mice but not pseudopregnant mice. To determine potential function of uterine gap junctions in embryo implantation, carbenoxolone (CBX), a broad gap junction blocker, was injected intraperitoneally (100 mg/kg) or via local uterine fat pad (10 mg/kg) into pregnant mice on D3 at 1800 h, a few hours before embryo attachment to LE. These CBX treatments disrupted embryo implantation, suggesting local effects of CBX in the uterus. However, intraperitoneal injection of 100 mg/kg glycyrrhizic acid, which shares similar structure and multiple properties with CBX but is ineffective in blocking gap junctions, did not affect embryo implantation. CBX also inhibited oil-induced artificial decidualization, concomitant with suppressed molecular changes and ultrastructural transformations associated with uterine preparation for embryo implantation, underscoring the adverse effect of CBX on uterine preparation for embryo implantation. These data demonstrate that uterine gap junctions are important for embryo implantation. Summary sentence: Broad gap junction blocker carbenoxolone suppresses uterine molecular changes and ultrastructural transformations associated with preparation for embryo implantation and disrupts embryo implantation.