Nuevos enfoques del proceso de vascularización en la gestación temprana. Rol del LPA y su receptor LPA3 en la vascularización de la interfase materno-fetal.

BELTRAME JS; RIBEIRO ML; FRANCHI AM; SORDELLI MS

Buenos Aires

Congreso; X Congreso de la Sociedad Argentina de Endocrinología Ginecológica y Reproductiva; 2016

Objective:Successful implantation and placentation requires that extravillouscytotrophoblast acquires an endovascular phenotype and remodels uterine spiralarteries. Defects in this mechanism correlate with severe obstetriccomplications as implantation failure and preeclampsia. Lysophosphatidic acid(LPA) participates in embryo implantation and contributes to vascularphysiology in different biological systems. However, the role of LPA ontrophoblast endovascular transformation has not been studied.Approachand results: Due to difficulties in studying human pregnancy in vivo, weadopted a pharmacological approach in vitro to investigate LPA action invarious aspects of trophoblast endovascular response, such as the formation ofendothelial capillary-like structures, migration and proliferation. TheHTR-8/SVneo cell line established from human first trimester cytotrophoblastwas used as a trophoblast model. LPA increased HTR-8/SVneo tube formation,migration (wound healing assay and phalloidin staining) and proliferation (MTTassay). LPA G protein-coupled receptors, LPA1 and LPA3, were expressed inHTR-8/SVneo. By using selective antagonists, we showed that enhancedtubulogenesis was mediated by LPA3. In addition, cyclooxygenase-2 and induciblenitric oxide synthase pathways participated in LPA-stimulated tubulogenesis,being inducible nitric oxide synthase activated downstream cyclooxygenase-2.Furthermore, prostaglandin E2 and a nitric oxide donor (SNAP) increasedtrophoblast tube formation in a concentration-dependent manner. Finally, weobserved that cyclooxygenase-2 and inducible nitric oxide synthase werelocalized in the nucleus, and LPA did not modify their cellular distribution.Conclusions:Our results show that LPA-triggered regulatory pathways promote trophoblastendovascular response in vitro, suggesting a new role for LPA during spiralartery remodeling at the maternal-fetal interface.