Simulated ischaemia/reperfusion impairs trophoblast function through divergent oxidative stress- and MMP-9-dependent mechanisms.

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioscience Reports Pub Date : 2024-10-30 DOI:10.1042/BSR20240763
Aaron Barron, Jetro Tuulari, Linnea Karlsson, Hasse Karlsson, Gerard W O'Keeffe, Cathal M McCarthy
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Abstract

Early-onset pre-eclampsia is believed to arise from defective placentation in the 1st trimester, leading to placental ischaemia/reperfusion (I/R) and oxidative stress. However, our current understanding of the effects of I/R and oxidative stress on trophoblast function is ambiguous in part due to studies exposing trophoblasts to hypoxia instead of I/R, and which report conflicting results. Here we present a model of simulated ischaemia/reperfusion (SI/R) to recapitulate the pathophysiological events of early-onset PE, by exposing 1st trimester cytotrophoblast HTR-8/SVneo cells to a simulated ischaemia buffer followed by reperfusion. We examined different ischaemia and reperfusion times and observed that 1h ischaemia and 24h reperfusion induced an increase in reactive oxygen species (ROS) production (p < 0.0001) and oxygen consumption rate (p < 0.01). SI/R-exposed trophoblast cells exhibited deficits in migration, proliferation and invasion (p < 0.01). While the deficits in migration and proliferation were rescued by antioxidants, suggesting a ROS-dependent mechanism, the loss of invasion was not affected by antioxidants, which suggests a divergent ROS-independent pathway. In line with this, we observed a decrease in MMP-9, the key regulatory enzyme necessary for trophoblast invasion (p < 0.01), which was similarly unaffected by antioxidants, and pharmacological inhibition of MMP-9 replicated the phenotype of deficient invasion (p < 0.01). Collectively, these data demonstrate that I/R impairs trophoblast migration and proliferation via a ROS-dependent mechanism, and invasion via a ROS-independent loss of MMP-9, disambiguating the role of oxidative stress and providing insights into the response of trophoblasts to I/R in the context of early-onset PE.

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模拟缺血/再灌注通过不同的氧化应激和 MMP-9 依赖性机制损害滋养层功能。
早发型子痫前期被认为是由于妊娠头三个月胎盘功能缺陷导致胎盘缺血/再灌注(I/R)和氧化应激引起的。然而,我们目前对缺血再灌注和氧化应激对滋养细胞功能影响的认识并不明确,部分原因是有研究将滋养细胞暴露于缺氧而非缺血再灌注环境中,这些研究报告的结果相互矛盾。在这里,我们提出了一种模拟缺血/再灌注(SI/R)模型,通过将怀孕三个月的滋养层细胞 HTR-8/SVneo 暴露于模拟缺血缓冲液中,然后进行再灌注,来再现早期 PE 的病理生理事件。我们研究了不同的缺血和再灌注时间,观察到缺血1小时和再灌注24小时会导致活性氧(ROS)生成增加(p < 0.0001)和耗氧量增加(p < 0.01)。SI/R暴露的滋养层细胞在迁移、增殖和侵袭方面表现出缺陷(p < 0.01)。虽然迁移和增殖的缺陷能被抗氧化剂所挽救,这表明这是一种依赖于 ROS 的机制,但侵袭的丧失不受抗氧化剂的影响,这表明这是一种不同的 ROS 非依赖性途径。与此相一致,我们观察到滋养细胞侵袭所必需的关键调控酶 MMP-9 减少(p < 0.01),同样不受抗氧化剂的影响,药理抑制 MMP-9 复制了侵袭不足的表型(p < 0.01)。总之,这些数据证明了I/R通过ROS依赖性机制损害滋养细胞的迁移和增殖,并通过MMP-9的ROS依赖性损失损害侵袭,从而明确了氧化应激的作用,并为早期PE背景下滋养细胞对I/R的反应提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Bioscience Reports
Bioscience Reports 生物-细胞生物学
CiteScore
8.50
自引率
0.00%
发文量
380
审稿时长
6-12 weeks
期刊介绍: Bioscience Reports provides a home for sound scientific research in all areas of cell biology and molecular life sciences. Since 2012, Bioscience Reports has been fully Open Access and publishes all papers under the liberal CC BY licence, giving the life science community quality research to share and discuss.Content before 2012 is subscription-only, and is accessible via archive purchase. Articles are assessed on soundness, providing a home for valid findings and data. We welcome papers that span disciplines (e.g. chemistry, medicine), including papers describing: -new methodologies -tools and reagents to probe biological questions -mechanistic details -disease mechanisms -metabolic processes and their regulation -structure and function -bioenergetics
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