Decidual cell FKBP51–progesterone receptor binding mediates maternal stress–induced preterm birth
| Autor: | Charles J. Lockwood, Bradley H. Sipe, Irina A. Buhimschi, Chinedu Nwabuobi, Kellie Larsen, Sefa Arlier, Frederick Schatz, Nihan Semerci, Umit A. Kayisli, Duygu Mutluay, Asli Ozmen, Xiaofang Guo, Ozlem Guzeloglu-Kayisli, Catalin S. Buhimschi |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Medical Sciences Progesterone receptor binding macromolecular substances environment and public health progesterone receptor Tacrolimus Binding Proteins Mice 03 medical and health sciences Maternal stress 0302 clinical medicine decidual cells Pregnancy Stress Physiological Internal medicine Progesterone receptor medicine Animals Decidual cells RNA Messenger Receptor Multidisciplinary integumentary system business.industry preterm birth Biological Sciences Oxytocin receptor FKBP51 030104 developmental biology Endocrinology maternal stress Models Animal Premature Birth Gestation Female FKBP5 Receptors Progesterone business 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. The genetics and molecular characteristics of PTB remain unclear. FKBP51 is an important mediator of the stress response and is implicated in the etiology of stress-related disorders. By combining studies in humans and Fkbp5−/− mice, we show that maternal stress up-regulates FKBP51 levels and enhances binding of FKBP51 to progesterone receptors. FKBP51 binding to progesterone receptors reduces progesterone receptor activity by causing functional progesterone withdrawal that induces PTB. In contrast, Fkbp5−/− mice are resistant to maternal stress–induced PTB and exhibit prolonged gestation. These findings provide molecular insights into stress-related PTB, indicating the importance of the potential use of inhibitor(s) against FKBP51 to treat PTB in future studies. 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. |
| Databáze: | OpenAIRE |
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