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首页> 外文期刊>Biochemical Pharmacology >Low-activity programming of the PDGFR beta/FAK pathway mediates H-type vessel dysplasia and high susceptibility to osteoporosis in female offspring rats after prenatal dexamethasone exposure
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Low-activity programming of the PDGFR beta/FAK pathway mediates H-type vessel dysplasia and high susceptibility to osteoporosis in female offspring rats after prenatal dexamethasone exposure

机译：PDGFRβ/ FAK路径的低活动编程介导H型血管发育不良，对产前地塞米松暴露后女性后代大鼠骨质疏松症的高敏感性

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摘要

Dexamethasone is a common synthetic glucocorticoid drug that can promote foetal lung maturity. An increasing number of studies have shown that prenatal dexamethasone exposure (PDE) can cause a variety of short-term and long-term hazards to offspring, including bone development toxicity. H-type vessels are a newly discovered subtype of blood vessels associated with promoted bone formation and maintenance of bone mass. In this study, we aimed to explore whether H-type blood vessels are involved in PDE-induced long bone development toxicity in offspring and its mechanism. In vivo, we injected dexamethasone (0.2 mg/kg.d) subcutaneously at gestational days 9?20 and observed the H-type vessel abundance and bone mass at different time points in the offspring rats. In vitro, we investigated the effect of dexamethasone (0, 20, 100, and 500 nM) on the tube formation function of rat bone marrow-derived endothelial progenitor cells (EPCs) and explored its mechanism. Our results showed that the adult PDE female offspring rats were susceptible to osteoporosis. In addition, PDE inhibited bone mass, H-type vessel formation and the expression of bone platelet-derived growth factor receptor ? (PDGFR?)/focal adhesion kinase (FAK) pathway-related genes in antenatal and postnatal female offspring. Moreover, PDE promoted the expression of bone glucocorticoid receptor (GR), CCAAT and enhancer binding protein ? (C/EBP?) and miR-34c in female foetuses. Dexamethasone suppressed the tube formation of rat bone marrow-derived EPCs and the activity of the PDGFR?/FAK pathway, which was mediated by GR/C/EBP?/miR34c signalling activation. In summary, PDE can cause H-type vessel dysplasia and high susceptibility to osteoporosis in female offspring, and its mechanism is related to the low-activity programming of the PDGFR?/FAK pathway induced by GR/C/EBP?/miR-34c signalling activation. This study enhances the understanding of the molecular mechanism of dexamethasone-induced bone development toxicity and provides new insights for exploring the early intervention and therapeutic targets of foetal-derived osteoporosis.
机译：地塞米松是一种常见的合成糖皮质激素药物，可促进胎儿肺成熟度。越来越多的研究表明，产前地塞米松暴露（PDE）可导致后代各种短期和长期危害，包括骨发育毒性。 H型血管是一种新发现的血管亚型，促进骨形成和骨量维持。在这项研究中，我们旨在探讨H型血管是否参与了后代的PDE诱导的长骨发育毒性及其机制。在体内，在妊娠期9℃下皮下注射地塞米松（0.2mg / kg.d），并观察到后代大鼠不同时间点的H型血管丰度和骨质。在体外，我们研究了地塞米松（0,20,100和500nm）对大鼠骨髓源性内皮祖细胞（EPC）的管形成功能的影响，并探讨了其机制。我们的研究结果表明，成人PDE女性后代大鼠易患骨质疏松症。此外，PDE抑制骨质量，H型容器形成和骨血小板衍生生长因子受体的表达？ （PDGFR？）/局灶性粘附激酶（FAK）产前雌性后代中的途径相关基因。此外，PDE促进了骨糖皮质激素受体（GR），CCAAT和增强子结合蛋白的表达？ （C / EBP？）和女性胎儿的miR-34c。地塞米松抑制了大鼠骨髓衍生的EPC的管形成和PDGFR的活性，由GR / C / EBP介导的介导的C / MIR34C信号传导激活。总之，PDE可导致H型血管发育不良和对骨后疏松症的高易感性，并且其机制与PDGFR的低活动编程有关，GR / C / EBP诱导的PDGFR？/ MIR-34C信令激活。该研究提高了对地塞米松诱导的骨发育毒性分子机制的理解，并为探索胎儿源疏松症的早期干预和治疗目标提供了新的见解。

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  • 来源
    《Biochemical Pharmacology》 |2021年第1期|共13页
  • 作者

    Shangguan Yangfan; Wu Zhixin; Xie Xingkui; Zhou Siqi; He Hangyuan; Xiao Hao; Liu Liang; Zhu Jiayong; Chen Haitao; Han Hui; Wang Hui; Chen Liaobin;

  • 作者单位

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

    Wuhan Univ Sch Basic Med Sci Dept Pharmacol Wuhan 430071 Peoples R China;

    Wuhan Univ Zhongnan Hosp Dept Orthoped Surg Wuhan 430071 Peoples R China;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    Dexamethasone; Platelet-derived growth factor receptor ?; H-type vessel; Osteoporosis; Intrauterine programming;

    机译：地塞米松;血小板衍生的生长因子受体？;H型血管;骨质疏松症;宫内节动脉编程;

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