Steroid hormones induce in vitro human first trimester trophoblast tubulogenesis by the lysophosphatidic acid pathway.

Successful implantation and placentation requires that extravillous cytotrophoblast acquires an endovascular phenotype and remodels uterine spiral arteries. Progesterone (P4) and estradiol (E2) control many of the placental functions, but their role in vascular remodeling remains controversial. Here, we investigated whether P4 and E2 regulate the acquisition of the human first trimester trophoblast endovascular phenotype, and the participation of the lysophosphatidic acid pathway. For this purpose, human first trimester HTR-8/SVneo cells were seeded on Geltrex and assayed for capillary-like tube formation. P4 and E2 increased HTR-8/SVneo tube formation in a concentration-dependent manner and this effect is mediated by the LPA3 receptor. Moreover, sex steroids increased the mRNA levels of the main enzyme that produce lysophosphatidic acid (lysophospholipase-D) but did not regulate LPA3 mRNA levels. Overall, we demonstrate that steroid hormones regulate HTR-8/SVneo trophoblast capillary-like structures formation and we propose that this process could be modulated directly or indirectly by mechanisms associated to the LPA/LPA3 pathway.