title: Transient {beta}2-adrenoceptor activation confers pregnancy loss by disrupting embryo spacing at implantation.
abstract: 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 β(2)-adrenoreceptor (β(2)-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 β(2)-AR antagonist or genetic ablation of β-AR. Similar β(2)-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 β(2)-AR activation is limited to the preimplantation period before embryo attachment. In vitro and in vivo studies demonstrated that the transient β(2)-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 β(2)-AR activation at early pregnancy provided a molecular clue in explaining how maternal stress at early stages could adversely affect the pregnancy outcome.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hongying
authors.initials: H
authors.lastname: Peng
authors.forename: Li
authors.initials: L
authors.lastname: Lei
authors.forename: Haibin
authors.initials: H
authors.lastname: Kuang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Lina
authors.initials: L
authors.lastname: Ning
authors.forename: Yujing
authors.initials: Y
authors.lastname: Cao
authors.forename: Enkui
authors.initials: E
authors.lastname: Duan
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism* / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D010064:Embryo Implantation; D020964:Embryo Loss / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D011247:Pregnancy; D011256:Pregnancy Outcome; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D018343:Receptors, Adrenergic, beta-2; D017868:Cyclic AMP-Dependent Protein Kinases