TROPHOBLAST BEHAVIOR AND BEYOND: ROLE OF REPRODUCTIVE BIOACTIVE LIPIDS AT THE MATERNAL-FETAL INTERFACE.

SORDELLI, MS; BELTRAME, JS; CAÑUMIL, VA; RIBEIRO, ML

Congreso; Reunión conjunta de sociedades de biociencia; 2017

An intricate molecular dialogue between trophoblast and uterus initiates the process ofimplantation, by which the embryo attaches to the lining of the uterus. After implantation,trophoblast cells begin a proliferative, migrating and invasive process infiltrating the decidua,remodeling uterine vasculature and connecting the mother blood stream with the fetus. Theseevents are accomplished by molecular and cellular interactions controlled by the maternal-fetalinterface microenvironment and may fail in certain obstetric complications such aspreeclampsia, intrauterine growth restriction and implantation failure.Several years ago, it has been observed that there is a change in the lipid composition at theluminal epithelium adjacent to the area where the blastocyst is attached. This change isinterpreted as a mobilization of precursors for the synthesis of lipid molecules that participate inangiogenesis and in the transformation of endometrial fibroblasts into decidual cells. Hence,novel insights with respect to roles played by the participation of lipids in the establishment ofpregnancy have sparked a renewed interest in understanding them no longer as simplestructural components of the membranes but as reproductive bioactive mediators.In this sense, lysophosphatidic acid (LPA) and prostaglandins play a major role in embryoimplantation. LPA has pleiotropic functions by binding to six G-protein coupled receptors.Prostaglandins have a pivotal role in decidualization and vascularization, two main processesduring trophoblast migration and invasion. We have previously reported that LPA augments theproduction of cyclooxygenase-2 derived prostaglandin E2 in the rat uterus during the window ofimplantation. Trophoblast cells are the main source of LPA in human first trimester, suggestingthat LPA actively participates in trophoblast functions.Defects in trophoblast migration and invasion are particularly vulnerable to failure during embryoimplantation resulting in pregnancy complications. Therefore, we aimed to investigate the role ofLPA on human first trimester trophoblast ́s functions and its interaction with prostaglandin E2.To achieve our experiments, we use a well-known immortalized human first trimestertrophoblast cell line HTR-8/SVneo. We design a pharmacological strategy using selective andbroad range LPA receptors antagonists and cyclooxygenase inhibitors. First, we characterizethe mRNA expression of LPA receptors and the enzyme Lysophospholipase-D, the mainenzyme involved in LPA synthesis and its principal source during gestation are the placentaltrophoblast. We observed that LPA stimulates both invasion and migration through LPA1-LPA4receptors (p<0.05), but does not modify proliferation. Then we found that cyclooxygenase-2derived prostaglandins mediate the increase triggered by LPA on trophoblasts cells sincecyclooxygenase inhibitors diminish LPA increased migration (p<0.05). Interestingly, LPAstimulates prostaglandin E2 production (p<0.05) and immunocytochemistry experimentssuggest that trophoblast cells stain positive for cyclooxygenase-1 and 2 in the cytoplasm andplasma membrane.Overall, these results demonstrate that LPA and prostaglandin E2 perform primordial functionsat the maternal-fetal interface modulating trophoblast invasion and migration by a prostaglandin-mediated mechanism triggered via LPA. Our findings contribute to better understand thesignificance of LPA signaling in the trophoblast behavior that lead to a successful pregnancy.