PSI-9 Disrupting Cxcl12-Cxcr4 Chemokine Axis at the Fetal-Maternal Interface During Implantation Results in Altered Expression of Angiogenic and Insulin-Like Growth Factors in Ovine Placenta Midgestation

Abstract Placental dysfunction is a fundamental cause of intrauterine growth restriction, and fetal morbidity and mortality in livestock. Though causes of placental dysfunction are not well characterized, origin of disease transpires during placental development (placentation). The C-X-C motif chemokine ligand 12 (CXCL12) working through its receptor CXCR4 is implicated in placentation but precise roles of this axis are unclear. Using an in vivo sheep model, we demonstrated that suppressing CXCL12-CXCR4 signaling at the fetal-maternal interface reduces placental vascularization. We hypothesized these negative impacts early in gestation would result in compromised placental development and vascularization at midgestation. To test, onday 12 post-breeding, osmotic pumps were surgically installed in 22 ewes and delivered either CXCR4 inhibitor (AMD3100) at 1.5X dose, (n=8) or 3X dose (n=8) or saline (n=6) into the uterine lumen ipsilateral to the corpus luteum for 14 days. On day 90 placental tissues were collected and maternal and fetal placenta components separated and analyzed. The objectives were to determine if suppressing CXCL12-CXCR4 actions at the fetal-maternal interface during implantation results in reduced placental and vascular development at midgestation. Gene expression for angiogenic factors and members of the insulin-like growth factor family were analyzed using Real-time qPCR. Of the targets tested, mRNA expression was significantly altered by AMD3100 treatment for the vascular endothelial growth factor receptors (FLT-1 and KDR) primarily in maternal placenta. Expression of insulin-like growth factors 1 and 2, IGF-binding protein 3, and placental lactogen were significantly altered in fetal placenta with AMD3100 treatment compared to control. Our preliminary data underscore the importance of CXCL12-CXCR4 signaling during placentation and provide strong evidence that altering CXCL12-mediated signaling during early placentation induces enduring placental effects manifesting later in gestation. A greater understanding of CXCL12/CXCR4 functions may reveal methods to improve reproductive success and fetal health.