National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China.
Department of Obstetrics, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, China.
Exp Mol Med. 2023 Jan;55(1):240-252. doi: 10.1038/s12276-023-00927-z. Epub 2023 Jan 18.
Production of estradiol (E2) by the placenta during human pregnancy ensures successful maintenance of placental development and fetal growth by stimulating trophoblast proliferation and the differentiation of cytotrophoblasts into syncytiotrophoblasts. Decreased levels of E2 are closely associated with obstetrical diseases such as preeclampsia (PE) in the clinic. However, the mechanisms underlying the inhibition of placental E2 biosynthesis remain poorly understood. Here, we report that regulator of G-protein signaling 2 (RGS2) affects E2 levels by regulating aromatase, a rate-limiting enzyme for E2 biosynthesis, by using human trophoblast-derived JEG-3 cells and human placental villus tissues. RGS2 enhanced the protein degradation of the transcription factor heart and neural crest derivatives expressed 1 (HAND1) by suppressing ubiquitin-specific protease 14 (USP14)-mediated deubiquitination of HAND1, resulting in the restoration of HAND1-induced trans-inactivation of the aromatase gene and subsequent increases in E2 levels. However, aromatase bound to RGS2 and repressed RGS2 GTPase activating protein (GAP) activity. Moreover, we observed a positive correlation between RGS2 and aromatase expression in clinical normal and preeclamptic placental tissues. Our results uncover a hitherto uncharacterized role of the RGS2-aromatase axis in the regulation of E2 production by human placental trophoblasts, which may pinpoint the molecular pathogenesis and highlight potential biomarkers for related obstetrical diseases.
人类妊娠期间胎盘产生的雌二醇（E2）通过刺激滋养细胞增殖和滋养细胞向合体滋养细胞分化，确保胎盘发育和胎儿生长的成功维持。临床上，E2 水平降低与子痫前期（PE）等产科疾病密切相关。然而，胎盘 E2 生物合成抑制的机制仍知之甚少。在这里，我们报告了 G 蛋白信号调节因子 2（RGS2）通过调节芳香酶来影响 E2 水平，芳香酶是 E2 生物合成的限速酶，使用人滋养细胞来源的 JEG-3 细胞和人胎盘绒毛组织。RGS2 通过抑制泛素特异性蛋白酶 14（USP14）介导的 HAND1 去泛素化来增强转录因子心脏和神经嵴衍生物表达 1（HAND1）的蛋白降解，从而恢复 HAND1 诱导的芳香酶基因的反式失活，并随后增加 E2 水平。然而，芳香酶与 RGS2 结合并抑制 RGS2 GTP 酶激活蛋白（GAP）活性。此外，我们在临床正常和子痫前期胎盘组织中观察到 RGS2 和芳香酶表达之间存在正相关。我们的研究结果揭示了 RGS2-芳香酶轴在调节人胎盘滋养细胞 E2 产生中的作用，这可能指明了相关产科疾病的分子发病机制，并突出了潜在的生物标志物。
