PSIII-1 Late-Breaking: Fighting Fetal Morbidity at the Fetal-Maternal Interface One Chemokine Access at a Time

Abstract

Abstract Improper placentation is the root cause to intrauterine growth restriction (IUGR) and fetal mortality in livestock. This study aims to further characterize the importance of the C-X-C motif chemokine receptor 4 (CXCR4) and its ligand CXCL12 on placentation and fetal growth through potential impacts on the insulin-like growth factors (IGF) and their binding proteins (IGFBP1-3). CXCR4 and CXCL12 are implicated in placentation though the exact roles are unclear. The peptides insulin-like growth factors 1 and 2 have impacts on fetal growth, placental development, and trophoblast differentiation and if the IGFs are down regulated, a corresponding decrease in placenta and fetus size has been observed. The roles of the IGFs and their binding proteins in disease states like IUGR are not completely known but studies have demonstrated them to be contributing factors. Using an in-vivo sheep model we surgically inserted osmotic pumps on day 12 (d12) of gestation ipsilateral to the corpus luteum to deliver treatments into the uterus of bred ewes. Pumps delivered either saline (control) or AMD3100, the CXCR4 inhibitor at a 1x, 1.5x, or 3x dose into the uterine lumen over the course of 14 days. Our objective was to determine if disrupting the CXCL12/CXCR4 axis during implantation alters the expression of IGFs and their binding proteins in the placenta at mid and late gestation. At midgestation (d90) and late gestation (d135) placental and fetal samples were obtained for analysis. Of the targets tested, mRNA expression was significantly decreased by AMD3100 treatment for both IGF-1 (P = 0.05) and IGF-2 (P = 0.02) compared to control primarily in maternal placenta tissues on d135. For fetal tissue samples, d90 mRNA expression for IGF-1 (P = 0.04) IGFBP-2 (P = 0.02) and IGFBP-3 (P = 0.03) increased in the 3x AMD3100 treated group compared to the control while in d135 samples, IGF-1was significantly decreased (P = 0.04) by the 1x treatments compared to control. Our preliminary data show an importance of the CXCL12- CXCR4 signaling on placentation and that impairment of this axis may alter IGFs in multiple tissue types later in gestation. Insights into this chemokine axis will lead to a greater understanding of placental development and its importance to the health of mother and offspring.