Lysophosphatidic acid‐triggered pathways promote the acquisition of trophoblast endovascular phenotype in vitro |
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| Authors: | Jimena S Beltrame Micaela S Sordelli Vanesa A Cañumil Ana M Franchi María L Ribeiro |
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| Affiliation: | 1. Laboratory of Physiology and Pharmacology of Reproduction, Centre for Pharmacological and Botanical Studies (CONICET ? School of Medicine, University of Buenos Aires), Buenos Aires, Argentina;2. Laboratory of Physiopathology of Pregnancy and Labor, Centre for Pharmacological and Botanical Studies (CONICET ? School of Medicine, University of Buenos Aires), Buenos Aires, Argentina |
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| Abstract: | Successful implantation and placentation requires that extravillous cytotrophoblast acquires an endovascular phenotype and remodels uterine spiral arteries. Defects in this mechanism correlate with severe obstetric complications as implantation failure and preeclampsia. Lysophosphatidic acid (LPA) participates in embryo implantation and contributes to vascular physiology in different biological systems. However, the role of LPA on trophoblast endovascular transformation has not been studied. Due to difficulties in studying human pregnancy in vivo, we adopted a pharmacological approach in vitro to investigate LPA action in various aspects of trophoblast endovascular response, such as the formation of endothelial capillary‐like structures, migration, and proliferation. The HTR‐8/SVneo cell line established from human first trimester cytotrophoblast was used to model the acquisition of the endovascular phenotype by the invading trophoblast. LPA increased HTR‐8/SVneo tube formation, migration (wound healing assay and phalloidin staining) and proliferation (MTT assay). LPA G protein‐coupled receptors, LPA1 and LPA3, were expressed in HTR‐8/SVneo. By using selective antagonists, we showed that enhanced tubulogenesis was mediated by LPA3. In addition, cyclooxygenase‐2 and inducible nitric oxide synthase pathways participated in LPA‐stimulated tubulogenesis. Inducible nitric oxide synthase was activated downstream cyclooxygenase‐2. Furthermore, prostaglandin E2 and a nitric oxide donor (SNAP) increased trophoblast tube formation in a concentration‐dependent manner. Finally, we observed that cyclooxygenase‐2 and inducible nitric oxide synthase were localized in the nucleus, and LPA did not modify their cellular distribution. Our results show that LPA‐triggered regulatory pathways promote trophoblast endovascular response in vitro, suggesting a new role for LPA during spiral artery remodeling at the maternal‐fetal interface. |
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| Keywords: | cyclooxygenase‐2 endovascular trophoblast inducible nitric oxide synthase LPA3 receptor lysophosphatidic acid |
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