期刊
EBIOMEDICINE
卷 70, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2021.103536
关键词
preeclampsia; epigenetic clock; senescence; ageing
资金
- NIH [R01 HL136348, R37 AG013925, P01 AG062413, R01 DK119167]
- Henry and Emma Meyer Professorship in Molecular Genetics
Preeclamptic women experience accelerated epigenetic ageing and higher levels of senescence-related factors. Treatment with dasatinib rescues angiogenic potential of mesenchymal stem cells from preeclamptic pregnancies, promoting angiogenesis.
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 p16INK4A in adipose tissue and renal sections, and (iv) demonstrate decreased levels of urinary a-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. (C) 2021 The Author(s). Published by Elsevier B.V.
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