Decidual cell FKBP51–progesterone receptor binding mediates maternal stress–induced preterm birth

Abstract

Depression and posttraumatic stress disorder increase the risk of idiopathic preterm birth (iPTB); however, the exact molecular mechanism is unknown. Depression and stress-related disorders are linked to increased FK506-binding protein 51 (FKBP51) expression levels in the brain and/or FKBP5 gene polymorphisms. Fkbp5-deficient (Fkbp5−/−) mice resist stress-induced depressive and anxiety-like behaviors. FKBP51 binding to progesterone (P4) receptors (PRs) inhibits PR function. Moreover, reduced PR activity and/or expression stimulates human labor. We report enhanced in situ FKBP51 expression and increased nuclear FKBP51-PR binding in decidual cells of women with iPTB versus gestational age-matched controls. In Fkbp5+/+ mice, maternal restraint stress did not accelerate systemic P4 withdrawal but increased Fkbp5, decreased PR, and elevated AKR1C18 expression in uteri at E17.25 followed by reduced P4 levels and increased oxytocin receptor (Oxtr) expression at 18.25 in uteri resulting in PTB. These changes correlate with inhibition of uterine PR function by maternal stress–induced FKBP51. In contrast, Fkbp5−/− mice exhibit prolonged gestation and are completely resistant to maternal stress–induced PTB and labor-inducing uterine changes detected in stressed Fkbp5+/+ mice. Collectively, these results uncover a functional P4 withdrawal mechanism mediated by maternal stress–induced enhanced uterine FKBP51 expression and FKPB51-PR binding, resulting in iPTB.

Assessment of Seasonality and Extremely Preterm Birth in Denmark

“…However, warmer months in Denmark, which in our study were associated with the highest risk of extremely preterm birth, are likely characterized by greater physical activity owing to increases in leisure activities and commuting by bicycle. Modifiers associated with psychological stressors and inflammation may play a substantial role in the orchestration of parturition 37 and may help to explain why seasonal variation in psychological stressors may be important for the occurrence of extremely preterm birth. 38 …”

Preterm birth, stillbirth, and early neonatal mortality during the Danish COVID-19 lockdown

“…39 Reduced anxiety and stress may also play a role by influencing the expression of the chaperone protein FKBP51; which increases in response to stress and alters the oestrogen/progesterone ratio thus overcoming the progesterone effect which inhibits parturition. 40,41 Two, albeit nearly 30 year old, Danish studies showed an association between anxiety in gestational week 30, but not in week 16, and PTB, 42 and an association between very early PTB (< 34 weeks) and severe stressful events in mid-pregnancy, 43 respectively. Furthermore, leisure-time activity during pregnancy has been associated with reduced risk of PTB, 44 while hard work and hard physical activity during pregnancy could be increase the risk of PTB.…”

Regulation of Proinflammatory Molecules and Tissue Factor by SARS-CoV-2 Spike Protein in Human Placental Cells: Implications for SARS-CoV-2 Pathogenesis in Pregnant Women

“…After receiving IRB approval, placental specimens from SARS-Cov-2 infected mothers (n=3) who tested positive for COVID-19 in the third trimester and gestational age-matched normal pregnancies (n=3) were obtained from Clinical Pathology Laboratories at Tampa General Hospital. 5 μm formalin-fixed paraffin embedded placental sections were processed for immunohistochemistry as described previously ( 28 ). Briefly, after deparaffinization and rehydration, paraffin-embedded sections were boiled in 10 mM citric acid solution (pH: 6.0) for antigen retrieval for 20 min and incubated in 3% H 2 O 2 for endogenous peroxidase quenching for 10 min.…”