Decreased Placental FPR2 in Early Pregnancies That Later Developed Small-For-Gestation Age: A Potential Role of FPR2 in the Regulation of Epithelial-Mesenchymal Transition

Abstract

We reported earlier that an anti-inflammatory small peptide receptor-formyl peptide receptor-2 (FPR2) was significantly decreased in placentas from third trimester pregnancies complicated with fetal growth restriction (FGR), compared to placentas from uncomplicated control pregnancies, suggesting FPR2 may play a role in the development of FGR. The aim of this study is to investigate whether the actions of FPR2 alters placental growth process in humans. Accordingly, using small-for-gestation age (SGA) as a proxy for FGR, we hypothesize that FPR2 expression is decreased in first-trimester placentas of women who later manifest FGR, and contributes to aberrant trophoblast function and the development of FGR. Chorionic villus sampling (CVS) tissues were collected at 10-12 weeks gestation in 70 patients with singleton fetuses; surplus tissue was used. Real-time PCR and immunoassays were performed to quantitate FPR2 gene and protein expression. Silencing of FPR2 was performed in two independent, trophoblast-derived cell lines, HTR-8/<i>SVneo</i> and JEG-3 to investigate the functional consequences of FPR2 gene downregulation. <i>FPR2</i> mRNA relative to <i>18S rRNA</i> was significantly decreased in placentae from SGA-pregnancies (<i>n</i> = 28) compared with controls (<i>n</i> = 52) (<i>p</i> < 0.0001). Placental FPR2 protein was significantly decreased in SGA compared with control (<i>n</i> = 10 in each group, <i>p</i> < 0.05). Proliferative, migratory and invasive potential of the human placental-derived cell lines, HTR-8/<i>SVneo</i> and JEG-3 were significantly reduced in <i>siFPR2</i> treated cells compared with <i>siCONT</i> control groups. Down-stream signaling molecules, <i>STAT5B</i> and <i>SOCS3</i> were identified as target genes of FPR2 action in the trophoblast-derived cell lines and in SGA and control chorionic villous tissues. FPR2 is a novel regulator of key molecular pathways and functions in placental development, and its decreased expression in women destined to develop FGR reinforces a placental origin of SGA/FGR, and that it contributes to causing the development of SGA/FGR.