胎盘生长因子通过激活子宫内膜中的 NFAT5-SGK1 信号轴介导病理性子宫血管生成:对子痫前期发展的影响。

IF 4.3 2区 生物学 Q1 BIOLOGY
Janet P Raja Xavier, Toshiyuki Okumura, Melina Apweiler, Nirzari A Chacko, Yogesh Singh, Sara Y Brucker, Satoru Takeda, Florian Lang, Madhuri S Salker
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引用次数: 0

摘要

月经后,子宫螺旋动脉通过血管生成得到修复。这一过程由子宫内膜基质细胞(EnSCs)和内皮细胞之间的旁分泌通讯严格调控。这些过程中的任何分子畸变都可能导致妊娠并发症,包括流产或子痫前期(PE)。已知胎盘生长因子(PlGF)是导致病理性血管生成的一个因素,但对其机制仍知之甚少。在这项研究中,我们探讨了 PlGF 是否会通过破坏 EnSCs 和内皮旁分泌通讯来促进病理性子宫血管生成。我们观察到,PlGF 在 EnSCs 中介导了独立于补体的活化 T 细胞核因子 5(NFAT5)的激活。NFAT5激活了下游靶标,包括SGK1、HIF-1α和VEGF-A。使用质谱法和酶联免疫吸附法对来自 EnSCs 的 PlGF - 条件培养基(CM)进行深入鉴定后发现,VEGF-A 含量较低,而细胞外基质组织相关蛋白含量丰富。PlGF-CM 中的分泌因子通过下调 Notch-VEGF 信号,阻碍了内皮细胞(HUVECs)的正常血管生成线索。有趣的是,PlGF-CM 未能支持人胎盘(BeWo)细胞侵入 HUVEC 单层。抑制 EnSCs 中的 SGK1 可改善 HUVECs 的血管生成效应并促进 BeWo 的侵袭,这揭示了 SGK1 是调节 PlGF 介导的抗血管生成信号的关键中间体。综上所述,子宫内膜中紊乱的 PlGF-NFAT5-SGK1 信号传导可通过负向调节 EnSCs-内皮串联导致子宫微环境中血管质量低下,从而促进病理性子宫血管生成。综上所述,这种信号转导可能会影响滋养细胞的正常侵入,从而影响胎盘的形成,并可能与 PE 等并发症的风险增加有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Placental growth factor mediates pathological uterine angiogenesis by activating the NFAT5-SGK1 signaling axis in the endometrium: implications for preeclampsia development.

After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.

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来源期刊
Biological Research
Biological Research 生物-生物学
CiteScore
10.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: Biological Research is an open access, peer-reviewed journal that encompasses diverse fields of experimental biology, such as biochemistry, bioinformatics, biotechnology, cell biology, cancer, chemical biology, developmental biology, evolutionary biology, genetics, genomics, immunology, marine biology, microbiology, molecular biology, neuroscience, plant biology, physiology, stem cell research, structural biology and systems biology.
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