Placental ischemia in preeclampsia (PE) results in hypertension and intrauterine growth restriction (IUGR). Stimulation of soluble guanylate cyclase (sGC) reduces blood pressure in the clinically relevant reduced uterine perfusion pressure (RUPP) rat model of PE implicating involvement in RUPP-induced hypertension. However, the contribution of sGC in the development of IUGR in PE is not known. Thus, this study demonstrated the efficacy of Riociguat, a sGC stimulator, in IUGR reversion in the RUPP rat model of PE, and tested the hypothesis that improvement in fetal weight occurs in association with improvement in placental perfusion, placental morphology, and placental nutrient transport protein expression. Sham or RUPP surgery was performed at gestational day 14 (G14) with administration of vehicle (Sham or RUPP) or the sGC stimulator (Riociguat, 10mg/kg/day, s.c.) (sGC-treated) until G20. Fetal weight was reduced (p=0.004) at G20 in RUPP but not sGC-treated RUPP compared to Sham, the control group. At G20, uterine artery resistance index (UARI) was increased (p=0.010) in RUPP indicating poor placental perfusion; proportional junctional zone surface area was elevated (p=0.035) indicating impaired placental development. These effects were ameliorated in sGC-treated RUPP. Placental protein expression of nutrient transporter heart fatty acid binding protein (hFABP) was increased (p=0.008) in RUPP but not sGC-treated RUPP suggesting a compensatory mechanism to maintain normal neurodevelopment. Yet, UARI (p<0.001), proportional junctional zone surface area (p=0.013), and placental hFABP protein expression (p=0.008) were increased in sGC-treated Sham suggesting a potential adverse effect of Riociguat. Collectively, these results suggest sGC contributes to IUGR in PE.

中文翻译：

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可溶性鸟苷酸环化酶的刺激减少了胎盘缺血大鼠模型中的宫内生长限制

先兆子痫 (PE) 中的胎盘缺血导致高血压和宫内生长受限 (IUGR)。可溶性鸟苷酸环化酶 (sGC) 的刺激降低了 PE 的临床相关降低的子宫灌注压 (RUPP) 大鼠模型中的血压，这与 RUPP 诱发的高血压有关。然而，sGC 在 PE 中 IUGR 发展中的贡献尚不清楚。因此，本研究证明了 sGC 刺激剂 Riociguat 在 PE 的 RUPP 大鼠模型中的 IUGR 逆转中的功效，并检验了胎儿体重的改善与胎盘灌注、胎盘形态和胎盘营养转运的改善相关的假设蛋白质表达。在妊娠第 14 天 (G14) 进行假手术或 RUPP 手术，给予载体（假手术或 RUPP）或 sGC 刺激剂（Riociguat，10mg/kg/天，皮下）（经 sGC 处理）直至 G20。与对照组 Sham 相比，在 G20 时，RUPP 中的胎儿体重减少（p = 0.004），但 sGC 处理的 RUPP 没有。在 G20 时，RUPP 中的子宫动脉阻力指数 (UARI) 增加 (p=0.010)，表明胎盘灌注不良；比例连接区表面积升高（p=0.035）表明胎盘发育受损。这些效果在 sGC 处理的 RUPP 中得到改善。RUPP 中营养转运体心脏脂肪酸结合蛋白 (hFABP) 的胎盘蛋白表达增加 (p=0.008)，但 sGC 处理的 RUPP 未增加，这表明维持正常神经发育的代偿机制。然而，UARI (p<0.001)、比例连接区表面积 (p=0.013) 和胎盘 hFABP 蛋白表达 (p=0. 008) 在 sGC 处理的 Sham 中增加，表明 Riociguat 的潜在不利影响。总的来说，这些结果表明 sGC 有助于 PE 中的 IUGR。