Supplemental Digital Content is available in the text. Cascade-specific termination of G protein signaling is catalyzed by the RGS (regulator of G protein signaling) family members, including RGS2. Angiotensin, vasopressin, and endothelin are implicated in preeclampsia, and RGS2 is known to inhibit G protein cascades activated by these hormones. Mutations in RGS2 are associated with human hypertension and increased risk of developing preeclampsia and its sequelae. RGS family members are known to influence maternal vascular function, but the role of RGS2 within the placenta has not been explored. Here, we hypothesized that reduced expression of RGS2 within the placenta represents a risk factor for the development of preeclampsia. Although cAMP/CREB signaling was enriched in placentas from human pregnancies affected by preeclampsia compared with clinically matched controls and RGS2 is known to be a CREB-responsive gene, RGS2 mRNA was reduced in placentas from pregnancies affected by preeclampsia. Experimentally reducing Rgs2 expression within the feto-placental unit was sufficient to induce preeclampsia-like phenotypes in pregnant wild-type C57BL/6J mice. Stimulation of RGS2 transcription within immortalized human HTR8/SVneo trophoblasts by cAMP/CREB signaling was discovered to be dependent on the activity of histone deacetylase activity, and more specifically, HDAC9 (histone deacetylase-9), and HDAC9 expression was reduced in placentas from human pregnancies affected by preeclampsia. We conclude that reduced expression of RGS2 within the placenta may mechanistically contribute to preeclampsia. More generally, this work identifies RGS2 as an HDAC9-dependent CREB-responsive gene, which may contribute to reduced RGS2 expression in placenta during preeclampsia.

中文翻译：

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胎盘中 RGS2（G 蛋白信号转导调节剂 2）的 mRNA 表达降低与人类先兆子痫有关，并足以引起小鼠疾病的特征

补充数字内容在文本中可用。G 蛋白信号转导的级联特异性终止由 RGS（G 蛋白信号转导调节剂）家族成员催化，包括 RGS2。血管紧张素、加压素和内皮素与先兆子痫有关，已知 RGS2 可抑制由这些激素激活的 G 蛋白级联反应。RGS2 的突变与人类高血压和发生先兆子痫及其后遗症的风险增加有关。已知 RGS 家族成员会影响母体血管功能，但尚未探索 RGS2 在胎盘中的作用。在这里，我们假设胎盘内 RGS2 的表达降低是先兆子痫发展的危险因素。尽管与临床匹配的对照相比，受先兆子痫影响的人类妊娠的胎盘中富含 cAMP/CREB ​​信号，并且已知 RGS2 是 CREB ​​响应基因，但 RGS2 mRNA 在受先兆子痫影响的妊娠的胎盘中减少。通过实验降低胎儿-胎盘单位内的 Rgs2 表达足以在怀孕的野生型 C57BL/6J 小鼠中诱导先兆子痫样表型。发现 cAMP/CREB ​​信号传导对永生化人 HTR8/SVneo 滋养层细胞内 RGS2 转录的刺激依赖于组蛋白去乙酰化酶活性，更具体地说，HDAC9（组蛋白去乙酰化酶-9），并且 HDAC9 在人胎盘中的表达降低受先兆子痫影响的怀孕。我们得出结论，胎盘内 RGS2 的表达降低可能在机制上导致先兆子痫。更一般地说，这项工作将 RGS2 鉴定为 HDAC9 依赖性 CREB ​​反应基因，这可能有助于先兆子痫期间胎盘中 RGS2 的表达降低。