Transient {beta}2-adrenoceptor activation confers pregnancy loss by disrupting embryo spacing at implantation.
Transient {beta}2-adrenoceptor activation confers pregnancy loss by disrupting embryo spacing at implantation.
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DOI：
10.1074/jbc.m110.197202
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发表时间：
2011-02-11
期刊：
影响因子：
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通讯作者：
Duan E
中科院分区：
文献类型：
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作者：
Chen Q;Zhang Y;Peng H;Lei L;Kuang H;Zhang L;Ning L;Cao Y;Duan E
妊娠丢失是一个严重的社会和医学问题，其中一个重要原因与妊娠早期的异常胚胎植入有关。然而，胚胎植入过程是否以及如何受到环境因素的影响，如应激诱导的交感神经激活仍然是一个谜。在这里，我们报告了一个意想不到的，短暂的影响，β2-肾上腺素受体（β2-AR）激活（第4天交配后）在破坏胚胎间距在植入，导致显着增加中期妊娠丢失。β2-AR拮抗剂预处理或β-AR基因敲除可预防胚胎间隔异常。在交配后第5天，当着床位点已经建立时，类似的β2-AR激活并不影响胚胎间隔或妊娠结局，表明β2-AR激活的不良影响仅限于胚胎附着前的植入前期。体外和体内研究表明，短暂的β2-AR激活消除了正常的植入前子宫收缩力，而不会对囊胚质量产生不利影响。收缩性抑制由cAMP-PKA通路的激活介导，并伴随着lpa 3的特异性下调，lpa 3是先前发现对子宫收缩和胚胎间隔至关重要的基因。这些结果表明，正常的子宫收缩介导的正确的宫内胚胎分布是成功的继续妊娠的关键。妊娠早期β2-AR的异常激活为解释早期母体应激如何对妊娠结局产生不利影响提供了分子线索。
Pregnancy loss is a serious social and medical issue, with one important cause associated with aberrant embryo implantation during early pregnancy. However, whether and how the process of embryo implantation is affected by environmental factors such as stress-induced sympathetic activation remained elusive. Here we report an unexpected, transient effect of β2-adrenoreceptor (β2-AR) activation (day 4 postcoitus) in disrupting embryo spacing at implantation, leading to substantially increased midterm pregnancy loss. The abnormal embryo spacing could be prevented by pretreatment of β2-AR antagonist or genetic ablation of β-AR. Similar β2-AR activation at day 5 postcoitus, when implantation sites have been established, did not affect embryo spacing or pregnancy outcome, indicating that the adverse effect of β2-AR activation is limited to the preimplantation period before embryo attachment. In vitro and in vivo studies demonstrated that the transient β2-AR activation abolished normal preimplantation uterine contractility without adversely affecting blastocyst quality. The contractility inhibition is mediated by activation of the cAMP-PKA pathway and accompanied by specific down-regulation of lpa3, a gene previously found to be critical for uterine contraction and embryo spacing. These results indicated that normal uterine contraction-mediated correct intrauterine embryo distribution is crucial for successful ongoing pregnancy. Abnormal β2-AR activation at early pregnancy provided a molecular clue in explaining how maternal stress at early stages could adversely affect the pregnancy outcome.