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Hypoxia-inducible factor 1 signaling drives placental aging and can elicit inflammatory changes in uterine myocytes

ABSTRACT: Placental aging has been proposed to promote labor onset, but specific mechanisms remain elusive. An unbiased transcriptomic analysis of healthy mouse placenta revealed that hypoxia-inducible factor 1 (HIF-1) stabilization is a hallmark of advanced gestational timepoints, accompanied by mitochondrial dysfunction and cellular senescence. We validated these gestational age-associated changes through similar findings in human placenta. In parallel in primary mouse trophoblasts and human choriocarcinoma JAR cells, we modeled HIF-1 induction using prolyl hydroxylase inhibitors cobalt chloride (CoCl2) and dimethyloxalylglycine (DMOG), and demonstrated that mitochondrial dysfunction and cellular senescence occur secondary to HIF-1 stabilization. Whole transcriptome analysis revealed that HIF-1 stabilization in JAR cells recapitulated the dysregulation of several pathways observed in aged placenta. Further, conditioned media from cultured trophoblasts following HIF-1 induction is sufficient to induce a contractile phenotype in immortalized uterine myocytes, suggesting a mechanism by which the aging placenta may help drive the transition from uterine quiescence to contractility at the onset of labor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199278 | GEO | 2022/03/29

REPOSITORIES: GEO

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