CONICET | Buscador de Institutos y Recursos Humanos

Successful implantation requires that the invadingtrophoblast acquires an endovascular phenotype and remodels uterine spiralarteries. Defects in this mechanism correlate with obstetric complications asimplantation failure and preeclampsia. Lysophosphatidic acid (LPA) participatesin embryo implantation and contributes to vascular physiology in differentbiological systems. However, the role of LPA on vascular processes at the implantationsite has not been investigated. We adopted an in vitro and an in vivopharmacological approach to study LPA action on trophoblast endovascularresponse and uterine transformation. The HTR-8/SVneo cell line (H8) was used tomodel the acquisition of the trophoblast endovascular phenotype. LPA (10 µM) increasedH8 tube formation (6h), migration (wound healing, 18h) and proliferation (MTTassay, 48h) (p<0.05). By using selective antagonists, we showed that enhancedtubulogenesis was mediated by LPA3 receptor. In addition, COX-2 and iNOSpathways participated in LPA-stimulated tubulogenesis, being nitric oxide thelast effector. When we investigated if the master hormones that orchestratecrucial events at the implantation sites, modulate trophoblast angiogenesis viaLPA/LPA3, we observed that estradiol (10-5 M) + progesterone (10-7M) increased H8 tube formation via LPA3 (p<0.05). The interactionbetween the trophoblast and the endothelium is relevant during the remodelingof the spiral arteries. We observed that trophoblast LPA-triggered secretedfactors increased the migration of the EA.hy926 endothelial cell line (p<0.05).Finally, the administration of a selective LPA3 antagonist to Wistar rats inday 5 of gestation increased the rate of embryo resorption (60%) associated tomacro and microvascular defects. Our results demonstrate a new role for LPAduring spiral artery remodeling at the maternal-fetal interface, and could helpto understand obstetric complications as implantation failure and preeclampsia.