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1.
Biol Reprod ; 104(2): 418-429, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33074310

RESUMO

MicroRNA (miR)-210 is a well-known hypoxia-inducible small RNA. Increasing in vitro evidence demonstrates its involvement in regulating multiple behaviors of placental trophoblasts. However, direct in vivo evidence remains lacking. In the present study, we generated a miR-210-deficient mouse strain using CRISPR/Cas9 technology, in which miR-210 expression was markedly deficient in various tissues. Little influence on fertility rate and litter size was observed after the deletion of miR-210 in mice. Continuous exposure of pregnant mice to hypoxia (10.5% O2) from E6.5 to E10.5 or to E18.5 led to reduction in fetal weight, and such fetal weight loss was markedly worsened in miR-210-knockout dams. Analysis of the placental structure demonstrated the reduced expansion of placental spongiotrophoblast layer and hampered development of labyrinth fetal blood vessels in knockout mice compared to the wild-type controls upon hypoxia stimulation. The findings indicate that miR-210 participates in regulating placental adaptation to hypoxic stress during pregnancy.


Assuntos
Hipóxia/metabolismo , MicroRNAs/metabolismo , Oxigênio/administração & dosagem , Placenta/fisiologia , Adaptação Fisiológica , Animais , Sequência de Bases , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Knockout , MicroRNAs/genética , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Distribuição Aleatória , Distribuição Tecidual
2.
Endocrinology ; 161(11)2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32976565

RESUMO

Uterine surgical scarring is an increasing risk factor for adverse pregnant consequences that threaten fetal-maternal health. The detailed molecular features of scar implantation remain largely unknown. We aim to study the pathologic features of uterine surgical scarring and the mechanisms of compromised pregnancy outcomes of scar implantation. We generated a mouse model of uterine surgical scarring with a uterine incision penetrating the myometrium to endometrium to examine the pathologic changes and transcriptome profiles of uterine scarring at various postsurgery (PS) time points, as well as features of the feto-maternal interface during scar implantation. We found that uterine surgical scar recovery was consistently poor at PS3 until PS90, as shown by a reduced number of endometrial glands, inhibition of myometrial smooth muscle cell growth but excessive collagen fiber deposition, and massive leukocyte infiltration. Transcriptome annotation indicated significant chronic inflammation at the scarring site. At the peri-implantation and postimplantation stages, abnormal expression of various steroid-responsive genes at the scarring site was in parallel with lumen epithelial cell hyperplasia, inappropriate luminal closure, and disorientation of the implanted embryo, restricted stromal cell proliferation, and defective decidualization. High embryonic lethality (around 70%) before E10.5 was observed, and the small amount of survival embryos at E10.5 exhibited restricted growth and aberrant placenta defects including overinvasion of trophoblast cells into the decidua and insufficient fetal blood vessel branching in the labyrinth. The findings indicate that chronic inflammation and compromised responses to steroids in uterine scar tissues are the pivotal molecular basis for adverse pregnancy consequences of scar implantation.


Assuntos
Cicatriz/complicações , Endométrio/efeitos dos fármacos , Hormônios Esteroides Gonadais/farmacologia , Complicações na Gravidez/etiologia , Útero/lesões , Animais , Cicatriz/genética , Cicatriz/metabolismo , Cicatriz/patologia , Decídua/efeitos dos fármacos , Decídua/metabolismo , Decídua/patologia , Modelos Animais de Doenças , Implantação do Embrião/efeitos dos fármacos , Implantação do Embrião/fisiologia , Endométrio/lesões , Endométrio/patologia , Endométrio/fisiologia , Feminino , Camundongos , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/patologia , Complicações na Gravidez/fisiopatologia , Gravidez Ectópica/etiologia , Gravidez Ectópica/genética , Gravidez Ectópica/metabolismo , Gravidez Ectópica/patologia , Ferida Cirúrgica/complicações , Ferida Cirúrgica/genética , Ferida Cirúrgica/metabolismo , Ferida Cirúrgica/patologia , Doenças Uterinas/etiologia , Doenças Uterinas/fisiopatologia , Útero/efeitos dos fármacos , Útero/patologia , Útero/fisiologia
3.
Biol Reprod ; 102(3): 560-570, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-31616934

RESUMO

The pregnancy complication preeclampsia is directly associated with hypoxic stress and insufficient trophoblast cell differentiation. The hypoxia-inducible microRNA (miRNA), miR-210, has been identified as a significantly up-regulated miRNA in preeclamptic placenta, and evidence in other cell types has indicated a feedback regulation between miR-210 and hypoxia-inducible factor-1α (HIF-1α) under hypoxic condition. It remains unclear whether and how the feedback loop between miR-210 and HIF-1α may contribute to trophoblast dysfunction in preeclampsia. Here, we proved that cytoplasmic polyadenylation element-binding 2 (CPEB2) was a direct target of miR-210 in human trophoblast. CPEB2 could inhibit the translation of hypoxia-induced HIF-1α via directly binding the cytoplasmic polyadenylation element (CPE) site in the 3'-untranslated region (UTR) of HIF-1α mRNA. The increase in the HIF-1α level upon hypoxia treatment could be efficiently reversed by miR-210 inhibitor. In addition, CPEB2 was primarily expressed in villous syncytiotrophoblasts, and the suppression of trophoblast cell syncytialization by miR-210 could be significantly rescued by CPEB2 overexpression. In preeclamptic placenta, the expression of CPEB2 was evidently lower than normal pregnant control, and the miR-210 level was aberrantly higher and trophoblast syncytialization was limited. The findings revealed a positive feedback loop between miR-210 and HIF-1α that is mediated by CPEB2 in human trophoblasts, and demonstrated a mechanism underlying the insufficient trophoblast syncytialization in preeclampsia under hypoxic stress.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Proteínas de Ligação a RNA/metabolismo , Trofoblastos/metabolismo , Linhagem Celular , Vilosidades Coriônicas/metabolismo , Regulação para Baixo , Feminino , Humanos , Fosforilação , Gravidez
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