Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

Abstract

Most cases of pre-term labor have unknown cause, and the burden of preterm birth on neonatal and child health is immense. Placental aging has been proposed to promote labor onset, but specific mechanisms remain elusive. We report here findings stemming from an unbiased transcriptomic analysis of healthy mouse placenta, which 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. These results provide clear evidence for placental aging in normal pregnancy. Mechanistic dissection of this phenomenon further demonstrates how hypoxia in late gestation may be both a causal determinant of the mitochondrial dysfunction and senescence observed within the trophoblast as well as a trigger to induce uterine contraction.

Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human

“…Consistent with this, we saw evidence of placental senescence in normal murine pregnancy (figs. S8 to S10) (52). In the setting of genetic predisposition, as in patients with cardiomyopathy mutations (7)(8)(9) or the cardiac-specific PGC1a KO mice, even the typical SASP protein abundances likely suffice to induce cardiac dysfunction.…”

“…S19). Accumulating evidence suggests that various triggers, such as DNA damage, oxidative stress, ischemia, and other environmental stresses, can exacerbate placental senescence (43,51,52). Thus, targeting these upstream placental stressors could represent an additional approach to treating pregnancy-associated cardiovascular disease.…”