妊娠失敗給育齡婦女的家庭和身心健康都帶來嚴(yán)重傷害,，最近文獻(xiàn)統(tǒng)計,，妊娠失敗在全球育齡婦女中的比例高達(dá)25-40%，已成為當(dāng)今一個全球性的醫(yī)學(xué)-社會問題,。近年來基礎(chǔ)和臨床醫(yī)學(xué)的研究發(fā)現(xiàn)：多數(shù)妊娠失敗病人的病因都起源于胚胎植入時期的異常,，流行病學(xué)的研究也發(fā)現(xiàn)妊娠早期母體緊張焦慮與后續(xù)妊娠中出現(xiàn)的流產(chǎn)或妊娠綜合癥密切相關(guān)。然而,，母體在妊娠早期的緊張如何影響胚胎植入并導(dǎo)致后續(xù)妊娠流產(chǎn)的原因還不得而知,。
由于哺乳動物的子宮受到交感神經(jīng)的廣泛支配，動物所段恩奎領(lǐng)導(dǎo)的研究團(tuán)隊認(rèn)為：妊娠早期母體緊張導(dǎo)致的交感興奮可能會迅速直接作用于子宮的腎上腺素受體,，從而改變正常的子宮-胚胎的相互作用,。
該實驗室以小鼠為模型研究發(fā)現(xiàn)：如果早期妊娠小鼠在胚胎植入前一過性地激活β2腎上腺素受體可嚴(yán)重破壞胚泡在子宮內(nèi)的正常分布。在此情況下胚胎植入雖然能夠按時發(fā)生,，但由于植入位置的不正確,，妊娠中期出現(xiàn)大量胚胎流產(chǎn)或發(fā)育不良，最終導(dǎo)致小鼠產(chǎn)仔量顯著降低,。體內(nèi)外功能研究表明：這種一過性的β2腎上腺素受體激活對子宮內(nèi)的胚胎并無明顯不良影響,，卻嚴(yán)重破壞了該時期子宮的正常收縮，進(jìn)而導(dǎo)致進(jìn)入子宮的胚胎不能被運輸?shù)秸_的位置植入,。進(jìn)一步的研究發(fā)現(xiàn)β2腎上腺素受體激動導(dǎo)致子宮收縮抑制是通過下游cAMP-PKA信號通路所介導(dǎo),，并且和之前發(fā)現(xiàn)的另一個胚胎植入重要分子LPA3的特異下調(diào)有關(guān)。以上結(jié)果揭示胚胎植入前子宮正常收縮介導(dǎo)的宮內(nèi)胚胎正確定位對胚胎的后續(xù)發(fā)育具有深遠(yuǎn)的影響,，錯誤的胚胎植入位置會導(dǎo)致一系列連鎖反應(yīng),，引起妊娠失敗或妊娠疾病。
在人類妊娠中,，宮內(nèi)胚胎正確定位（子宮體的底部）的過程與小鼠有類似的機制,，均受子宮正常收縮的嚴(yán)格調(diào)控，如果植入位置異常將會導(dǎo)致流產(chǎn)或妊娠綜合癥（例如胎盤前置）,。母體在早孕時期的機體/心理緊張引起的交感興奮可能是導(dǎo)致子宮收縮異常及胚胎定位錯誤的一個原因,。
由于該研究還發(fā)現(xiàn)在小鼠中這種β2腎上腺素受體異常激活導(dǎo)致的妊娠不良影響能夠通過敲除β腎上腺素受體或給予β2腎上腺素受體拮抗劑進(jìn)行有效的挽救，故提示腎上腺素類藥物在調(diào)控植入前子宮的不正常收縮中具有潛在的臨床應(yīng)用前景,。
該研究于2011年2月11日發(fā)表于Journal of Biological Chemistry,，共同第一作者是段恩奎研究組的博士生陳琦和張瑩,。
本研究得到了國家“發(fā)育與生殖”重大科學(xué)研究計劃，中國科學(xué)院知識創(chuàng)新方向性項目和國家自然科學(xué)基金的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
J Biol Chem doi: 10.1074/jbc.M110.197202
Transient β2-Adrenoceptor Activation Confers Pregnancy Loss by Disrupting Embryo Spacing at Implantation*
Qi Chen?§,1, Ying Zhang?§,1, Hongying Peng?, Li Lei?§, Haibin Kuang?§, Li Zhang?§, Lina Ning?, Yujing Cao? and Enkui Duan?,2
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.
