Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Stem Cell Research, Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Sciences and NHS Blood and Transplant, University of Oxford, Oxford, UK.
Hypertension. 2018 Oct;72(4):937-945. doi: 10.1161/HYPERTENSIONAHA.118.11343. Epub 2018 Aug 20.
Offspring of hypertensive pregnancies are at increased risk of developing hypertension in adulthood. In the neonatal period they display endothelial cell dysfunction and altered microvascular development. MicroRNAs, as important endothelial cellular regulators, may play a role in this early endothelial dysfunction. Therefore we identified differential microRNA patterns in endothelial cells from offspring of hypertensive pregnancies and determined their role in postnatal vascular cell function. Studies were performed on human umbilical vein endothelial cell (HUVECs) samples from 57 pregnancies. Unbiased RNA-sequencing identified 30 endothelial-related microRNAs differentially expressed in HUVECs from hypertensive compared to normotensive pregnancies. Quantitative reverse transcription PCR (RT-qPCR) confirmed a significant higher expression level of the top candidate, miR-146a. Combined miR-146a targeted gene expression and pathway analysis revealed significant alterations in genes involved in inflammation, angiogenesis and immune response in the same HUVECs. Elevated miR-146a expression level at birth identified cells with reduced ability for vascular tube formation, which was rescued by miR-146a inhibition. In contrast, miR-146a overexpression significantly reduced vascular tube formation in HUVECs from normotensive pregnancies. Finally, we confirmed that mir146a levels at birth predicted microvascular development during the first three postnatal months. Offspring of hypertensive pregnancy have a distinct endothelial regulatory microRNA profile at birth, which is related to altered endothelial cell behaviour, and predicts patterns of microvascular development during the first three months of life. Modification of this microRNA profile can restore impaired vascular cell function.
高血压妊娠的后代在成年后患高血压的风险增加。在新生儿期，它们表现出内皮细胞功能障碍和微血管发育改变。微小 RNA 作为重要的内皮细胞调节因子，可能在这种早期内皮功能障碍中发挥作用。因此，我们鉴定了高血压妊娠后代内皮细胞中的差异微小 RNA 模式，并确定了它们在产后血管细胞功能中的作用。研究在 57 例妊娠的人脐静脉内皮细胞（HUVEC）样本中进行。无偏 RNA-seq 鉴定了高血压妊娠与正常血压妊娠的 HUVEC 中 30 个差异表达的内皮相关微小 RNA。定量逆转录 PCR（RT-qPCR）证实了 top 候选物 miR-146a 的表达水平显著升高。结合 miR-146a 靶向基因表达和通路分析，在相同的 HUVEC 中发现了参与炎症、血管生成和免疫反应的基因的显著改变。出生时升高的 miR-146a 表达水平确定了血管管腔形成能力降低的细胞，而 miR-146a 抑制可挽救这种能力。相反，miR-146a 在正常血压妊娠的 HUVEC 中过表达显著降低了血管管腔形成。最后，我们证实出生时的 mir146a 水平预测了出生后前三个月的微血管发育。高血压妊娠的后代在出生时具有独特的内皮调节微小 RNA 谱，与改变的内皮细胞行为有关，并预测了出生后前三个月的微血管发育模式。这种微小 RNA 谱的修饰可以恢复受损的血管细胞功能。
