Background

Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria and/or multisystem involvement. Disease-specific therapy has yet to be developed due to the lack of understanding of underlying mechanism(s). We postulate that accelerated ageing in general, and particularly cellular senescence, play a role in its pathophysiology.

Methods

We compared women with preeclampsia vs. normotensive pregnancies with respect to epigenetic markers of ageing and markers of senescence in tissues/organs affected by preeclampsia (blood, urine, adipose tissue, and kidney).

Findings

We demonstrate that preeclamptic compared to normotensive pregnant women: (i) undergo accelerated epigenetic ageing during pregnancy, as demonstrated by an “epigenetic clock”; (ii) exhibit higher levels/expression of senescence-associated secretory phenotype factors in blood and adipose tissue; (iii) display increased expression of p16^INK4A in adipose tissue and renal sections, and (iv) demonstrate decreased levels of urinary α-Klotho (an anti-ageing protein) at the time of delivery. Finally, we provide data indicating that pre-treatment with dasatinib, a senolytic agent, rescues the angiogenic potential of mesenchymal stem cells (MSC) obtained from preeclamptic pregnancies, and promotes angiogenesis, even under pro-inflammatory conditions.

Interpretation

Taken together, our results identify senescence as one of the mechanisms underpinning the pathophysiology of preeclampsia. Therapeutic strategies that target senescent cells may offer novel mechanism-based treatments for preeclampsia.

Funding

This work was supported by NIH grants, R01 HL136348, R37 AG013925, P01 AG062413, R01 DK11916, generous gifts from the Connor Fund, Robert J. and Theresa W. Ryan and from The George G. Beasley family, the Noaber Foundation, and the Henry and Emma Meyer Professorship in Molecular Genetics.

中文翻译：

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表观遗传和衰老标志物表明先兆子痫孕妇的加速衰老样状态

背景

先兆子痫是一种以蛋白尿和/或多系统受累为特征的妊娠特异性高血压疾病。由于缺乏对潜在机制的了解，尚未开发出针对疾病的治疗方法。我们假设一般加速衰老，特别是细胞衰老，在其病理生理学中起作用。

方法

我们将患有先兆子痫的女性与. 在受先兆子痫影响的组织/器官（血液、尿液、脂肪组织和肾脏）中的衰老表观遗传标志物和衰老标志物的正常血压妊娠。

发现

我们证明，与血压正常的孕妇相比，先兆子痫：（i）在怀孕期间经历加速的表观遗传衰老，如“表观遗传时钟”所示；(ii) 在血液和脂肪组织中表现出更高水平/表达的衰老相关分泌表型因子；(iii) 显示脂肪组织和肾切片中 p16 ^INK4A的表达增加，以及 (iv) 显示分娩时尿 α-Klotho（一种抗衰老蛋白）水平降低。最后，我们提供的数据表明，用达沙替尼（一种衰老清除剂）进行预处理可以挽救从先兆子痫妊娠中获得的间充质干细胞 (MSC) 的血管生成潜力，并促进血管生成，即使在促炎条件下也是如此。

解释

总之，我们的结果将衰老确定为支持先兆子痫病理生理学的机制之一。针对衰老细胞的治疗策略可能为先兆子痫提供新的基于机制的治疗方法。

资金

这项工作得到了 NIH 赠款、R01 HL136348、R37 AG013925、P01 AG062413、R01 DK11916、康纳基金、罗伯特 J. 和特蕾莎 W. 瑞安以及乔治 G. 比斯利家族、诺伯基金会和Henry 和 Emma Meyer 分子遗传学教授。