Department of Biomedical and Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
Int J Mol Sci. 2022 Jul 29;23(15):8426. doi: 10.3390/ijms23158426.
Placentation is one of the most important determinants for a successful pregnancy, and this is dependent on the process of trophoblast migration and invasion. Progesterone receptors (PGR) are critical effectors of progesterone (P4) signaling that is required for trophoblast migration and invasion conducive to a successful gestation. In immune complicated pregnancies, evidence has shown that abnormal placentation occurs because of aberrant expression of PGR. Therapeutic intervention with tacrolimus (FK506) was able to restore PGR expression and improve pregnancy outcomes in immune-complicated gestations; however, the exact mode of action of tacrolimus in assisting placentation is not clear. Here, we attempt to uncover the mode of action of tacrolimus by examining its effects on trophoblast invasion and migration in the human-derived extravillous trophoblast (EVT) cell line, the HTR-8/SVneo cells. Using a variety of functional assays, we demonstrated that low-dose tacrolimus (10 ng/mL) was sufficient to significantly (p < 0.001) stimulate the migration and invasion of the HTR-8/SVneo cells, inducing their cytosolic/nuclear progesterone receptor expression and activation, and modulating their Nitric Oxide (NO) production. Moreover, tacrolimus abrogated the suppressive effect of the NOS inhibitor Nω- Nitro-L-Arginine Methyl Ester (L-NAME) on these vital processes critically involved in the establishment of human pregnancy. Collectively, our data suggest an immune-independent mode of action of tacrolimus in positively influencing placentation in complicated gestations, at least in part, through promoting the migration and invasion of the first trimester extravillous trophoblast cells by modulating their NO production and activating their cytosolic/nuclear progesterone-receptors. To our knowledge, this is the first report to show that the mode of action of tacrolimus as a monotherapy for implantation failure is plausibly PGR-dependent.
胎盘形成是成功妊娠的最重要决定因素之一，这取决于滋养细胞迁移和浸润的过程。孕激素受体（PGR）是孕激素（P4）信号传导的关键效应物，对于滋养细胞迁移和浸润、促进成功妊娠至关重要。在免疫复杂的妊娠中，有证据表明异常的胎盘形成是由于 PGR 的异常表达所致。他克莫司（FK506）的治疗干预能够恢复免疫复杂妊娠中的 PGR 表达，并改善妊娠结局；然而，他克莫司在协助胎盘形成中的确切作用模式尚不清楚。在这里，我们试图通过研究他克莫司对人源性绒毛外滋养细胞（EVT）细胞系 HTR-8/SVneo 细胞的侵袭和迁移的影响来揭示他克莫司的作用模式。通过多种功能测定，我们证明低剂量他克莫司（10ng/ml）足以显著（p<0.001）刺激 HTR-8/SVneo 细胞的迁移和侵袭，诱导其胞质/核孕激素受体表达和激活，并调节其一氧化氮（NO）的产生。此外，他克莫司阻断了一氧化氮合酶抑制剂 Nω-硝基-L-精氨酸甲酯（L-NAME）对这些对人类妊娠建立至关重要的关键过程的抑制作用。总之，我们的数据表明，他克莫司在复杂妊娠中具有独立于免疫的作用模式，至少部分通过调节其一氧化氮的产生和激活其胞质/核孕激素受体来促进早期绒毛外滋养细胞的迁移和侵袭，从而积极影响胎盘形成。据我们所知，这是第一项表明他克莫司作为单一疗法治疗着床失败的作用模式可能依赖于 PGR 的报告。
