Interaction between Lysophosphatidic Acid, Prostaglandins and the Endocannabinoid System during the Window of Implantation in the Rat Uterus

MICAELA S. SORDELLI; JIMENA BELTRAME; CELLA MAXIMILIANO; MARÍA GRACIA GERVASI; SILVINA PEREZ MARTINEZ; JULIANA BURDET; ELSA ZOTTA; ANA FRANCHI; MARÍA LAURA RIBEIRO

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 10

1932-6203

Bioactive lipid molecules as lysophosphatidic acid (LPA), prostaglandins (PG) and endocannabinoids are importantmediators of embryo implantation. Based on previous published data we became interested in studying the interactionbetween these three groups of lipid derivatives in the rat uterus during the window of implantation. Thus, we adopteda pharmacological approach in vitro using LPA, DGPP (a selective antagonist of LPA3, an LPA receptor), endocannabinoids?receptor selective antagonists (AM251 and AM630) and non selective (indomethacin) and selective (NS-398) inhibitors ofcyclooxygenase-1 and 2 enzymes. Cyclooxygenase isoforms participate in prostaglandins? synthesis. The incubation of theuterus from rats pregnant on day 5 of gestation (implantation window) with LPA augmented the activity and the expressionof fatty acid amide hydrolase, the main enzyme involved in the degradation of endocannabinoids in the rodent uteri,suggesting that LPA decreased endocannabinoids? levels during embryo implantation. It has been reported that highendocannabinoids are deleterious for implantation. Also, LPA increased PGE2 production and cyclooxygenase-2 expression.The incubation of LPA with indomethacin or NS-398 reversed the increment in PGE2 production, suggesting thatcyclooxygenase-2 was the isoform involved in LPA effect. PGs are important mediators of decidualization andvascularization at the implantation sites. All these effects were mediated by LPA3, as the incubation with DGPP completelyreversed LPA stimulatory actions. Besides, we also observed that endocannabinoids mediated the stimulatory effect of LPAon cyclooxygenase-2 derived PGE2 production, as the incubation of LPA with AM251 or AM630 completely reversed LPAeffect. Also, LPA augmented via LPA3 decidualization and vascularization markers. Overall, the results presented heredemonstrate the participation of LPA3 in the process of implantation through the interaction with other groups of lipidmolecules, prostaglandins and endocannabinoids, which prepare the uterine milieu for embryo invasion during the windowof implantation.