Terstappen Fieke, Plösch Torsten, Calis Jorg J A, Ganzevoort Wessel, Pels Anouk, Paauw Nina D, Gordijn Sanne J, van Rijn Bas B, Mokry Michal, Lely A Titia
University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Obstetrics, Utrecht, The Netherlands.
University Medical Center Groningen, Department of Obstetrics and Gynaecology, University of Groningen, Groningen, The Netherlands.
J Trial Error. 2023 Sep 26:e16. doi: 10.36850/e16.
Fetal growth restricted (FGR) offspring are more susceptible to develop cardiovascular and renal disease. The potential therapeutic value of sildenafil to improve fetal growth has recently been evaluated in several randomized clinical trials. Here we investigate whether administration of sildenafil during pregnancies complicated by FGR influences fetal-placental programming profiles, especially related to cardiorenal development and disease.
We collected human umbilical vein endothelial cells (HUVECs) and placental tissue within the Dutch STRIDER trial, in which sildenafil versus placebo treatment were randomly assigned to pregnancies complicated by severe early-onset FGR. Differential expression of genes of these samples were studied by whole genome RNA-sequencing. In addition, we performed gene set enrichment analysis focused on cardiovascular and renal gene sets to examine differentially expressed gene sets related to cardiorenal development and health.
Our study showed similar gene expression profiles between treatment groups in HUVECs (n=12 sildenafil; n=8 placebo) and placentas (n=13 per group). Prenatal sildenafil exposure did not change cardiovascular or renal programming in pregnancies complicated by FGR. In placental tissue, prenatal sildenafil altered a few gene sets involved with the nitric oxide pathway potentially reflecting the mechanism of action of sildenafil. Prenatal sildenafil also upregulated gene sets related to immune pathways in placental tissue.
Overall, our study showed that sildenafil has the potential to alter placental (but not fetal) expression of gene sets related to immune pathways and did not support (in)direct reprogramming of cardiovascular or renal health in human pregnancies complicated by FGR.
胎儿生长受限（FGR）后代患心血管和肾脏疾病的风险更高。最近在几项随机临床试验中评估了西地那非改善胎儿生长的潜在治疗价值。在此，我们研究在合并FGR的妊娠期间给予西地那非是否会影响胎儿-胎盘编程谱，特别是与心脏和肾脏发育及疾病相关的编程谱。
我们在荷兰STRIDER试验中收集了人脐静脉内皮细胞（HUVECs）和胎盘组织，该试验将西地那非与安慰剂治疗随机分配给合并严重早发性FGR的妊娠。通过全基因组RNA测序研究这些样本中基因的差异表达。此外，我们进行了基因集富集分析，重点关注心血管和肾脏基因集，以检查与心脏和肾脏发育及健康相关的差异表达基因集。
我们的研究表明，HUVECs（西地那非组n = 12；安慰剂组n = 8）和胎盘（每组n = 13）治疗组之间的基因表达谱相似。产前暴露于西地那非并未改变合并FGR妊娠中的心血管或肾脏编程。在胎盘组织中，产前西地那非改变了一些与一氧化氮途径相关的基因集，这可能反映了西地那非的作用机制。产前西地那非还上调了胎盘组织中与免疫途径相关的基因集。
总体而言，我们的研究表明，西地那非有可能改变与免疫途径相关的胎盘（而非胎儿）基因集的表达，并且不支持对合并FGR的人类妊娠中的心血管或肾脏健康进行（直接）重编程。
