Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi, Tsu 5148507, Mie, Japan.
Int J Mol Sci. 2022 Jan 27;23(3):1474. doi: 10.3390/ijms23031474.
Fetal growth restriction (FGR) is a major cause of poor perinatal outcomes. Although several studies have been conducted to improve the prognosis of FGR in infants, no effective intrauterine treatment method has been established. This study aimed to use tadalafil, a phosphodiesterase 5 inhibitor (PDE5) inhibitor, as a novel intrauterine treatment and conducted several basic and clinical studies. The study investigated the effects of tadalafil on placental mTOR signaling. Tadalafil was administered to mice with L-NG-nitroarginine methyl ester (L-NAME)-induced FGR and associated preeclampsia (PE). Placental phosphorylated mTOR (p-mTOR) signaling was assessed by fluorescent immunohistochemical staining and Western blotting. The expression of p-mTOR was significantly decreased in mice with FGR on 13 days post coitum (d.p.c.) but recovered to the same level as that of the control on 17 d.p.c. following tadalafil treatment. The results were similar for 4E-binding protein 1 (4E-BP1) and S6 ribosomal (S6R) protein, which act downstream in the mTOR signaling pathway. We demonstrate that the tadalafil treatment of FGR in mice improved placental mTOR signaling to facilitate fetal growth. Our study provides the key mechanistic detail about the mode of action of tadalafil and thus would be helpful for future clinical studies on FGR.
胎儿生长受限（FGR）是围产儿预后不良的主要原因。尽管已经有几项研究致力于改善 FGR 婴儿的预后，但尚未建立有效的宫内治疗方法。本研究旨在使用磷酸二酯酶 5 抑制剂（PDE5）抑制剂他达拉非作为一种新型宫内治疗方法，并进行了几项基础和临床研究。该研究调查了他达拉非对胎盘 mTOR 信号的影响。将他达拉非施用于 L-NG-硝基精氨酸甲酯（L-NAME）诱导的 FGR 伴发先兆子痫（PE）的小鼠。通过荧光免疫组织化学染色和 Western blot 评估胎盘磷酸化 mTOR（p-mTOR）信号。在妊娠 13 天（d.p.c.）时，FGR 小鼠的 p-mTOR 表达显著降低，但在用他达拉非治疗后，在妊娠 17 天（d.p.c.）时恢复到与对照组相同的水平。在 mTOR 信号通路下游的 4E 结合蛋白 1（4E-BP1）和 S6 核糖体（S6R）蛋白的表达也有类似的结果。我们证明，他达拉非治疗 FGR 可改善胎盘 mTOR 信号，促进胎儿生长。我们的研究提供了他达拉非作用机制的关键细节，这将有助于未来对 FGR 的临床研究。
