We postulate that in women and other mammals, uterine quiescence is maintained by increased progesterone receptor (PR) activity, and that spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and negatively impact PR function. The mechanisms by which progesterone (P4)/PR blocks uterine contractility and the signals leading to the initiation of labor remain incompletely defined. In research funded by the current P01, we obtained compelling evidence that PR maintains myometrial quiescence throughout most of pregnancy by blocking activation of inflammatory pathways and inhibiting expression of 'contractile'genes. This likely occurs via direct inhibitory interaction of PR with inflammatory transcription factors (e.g. NF-KB), by PR upregulation of genes that inhibit inflammatory signaling and NF-KB activation (e.g. MAPK phosphatase I and kBa), and/or by PR modulation of microRNAs (miRNAs/miRs) that regulate expression of uterine 'contractile'and inflammatory genes. Near term, fetal (e.g. augmented surfactant protein-A [SP-A] secretion by fetal lung) and maternal (e.g. uterine stretch) signals stimulate migration of macrophages {M^) to the uterus where they activate inflammatory pathways leading to NF-KB activation. We suggest that activated uterine NF-KB upregulates uterine 'contractile'genes and negatively impacts the capacity of PR to maintain uterine quiescence, culminating in labor. Our findings suggest that PR function in myometrium is impaired near term by direct interaction with NF-KB, decreased expression of PR coactivators (e.g. steroid receptor coactivators [SRCs]), upregulation of truncated PR isoforms and increased expression of enzymes that metabolize P4 to inactive products. To further define mechanisms whereby PR inhibits myometrial contractility during preg nancy and by which inflammatory signaling upregulates contractile genes and represses PR function, the following research objectives are proposed: (1) elucidate differential roles of PR-A and PR-B isoforms and their posttranslational modification in transrepression of contractile gene expression in the myometrium;(2) define the epigenetic mechanisms that underlie the inhibitory effects of P4/PR and the stimulatory effects of proinflammatory cytokines on expression of uterine 'contractile'genes;(3) elucidate the roles of miRNAs and their targets in control of myometrial quiescence/ contractility, their regulation by P4 and by inflammatory mediators and their function as mediators of myometrial quiescence and contractility. We believe that this research will provide important insight into the mechanisms that underlie critical changes in PR function in pregnancy and labor and lead to novel therapeutic strategies to decrease the incidence of pretenn birth.
We propose that uterine quiescence throughout most of pregnancy is maintained by increased PR transcriptional activity and by suppression of inflammatory transcription factors and contractile genes. By contrast, labor initiated by proinflammatory signals from the fetus that both directly upregulate contractile genes and negatively impact PR function. It is anticipated that the proposed research will provide important insight into these mechanisms and, thereby, lead to the development of therapeutic strategies to prevent preterm labor and the morbidity and mortality associated with premature birth.
| Mahendroo, Mala (2018) Cervical hyaluronan biology in pregnancy, parturition and preterm birth. Matrix Biol : |
| Mendelson, Carole R; Montalbano, Alina P; Gao, Lu (2017) Fetal-to-maternal signaling in the timing of birth. J Steroid Biochem Mol Biol 170:19-27 |
| Chen, Chien-Cheng; Montalbano, Alina P; Hussain, Imran et al. (2017) The transcriptional repressor GATAD2B mediates progesterone receptor suppression of myometrial contractile gene expression. J Biol Chem 292:12560-12576 |
| Chigusa, Yoshitsugu; Kishore, Annavarapu Hari; Mogami, Haruta et al. (2016) Nrf2 Activation Inhibits Effects of Thrombin in Human Amnion Cells and Thrombin-Induced Preterm Birth in Mice. J Clin Endocrinol Metab 101:2612-21 |
| Gao, Lu; Wang, Gang; Liu, Wei-Na et al. (2016) Reciprocal Feedback Between miR-181a and E2/ER? in Myometrium Enhances Inflammation Leading to Labor. J Clin Endocrinol Metab 101:3646-3656 |
| Jimenez, Patricia T; Mainigi, Monica A; Word, R Ann et al. (2016) miR-200 Regulates Endometrial Development During Early Pregnancy. Mol Endocrinol 30:977-87 |
| Eskiocak, Ugur; Ramesh, Vijayashree; Gill, Jennifer G et al. (2016) Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma. Nat Commun 7:12336 |
| Gao, Lu; Rabbitt, Elizabeth H; Condon, Jennifer C et al. (2015) Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. J Clin Invest 125:2808-24 |
| Renthal, Nora E; Williams, Koriand'r C; Montalbano, Alina P et al. (2015) Molecular Regulation of Parturition: A Myometrial Perspective. Cold Spring Harb Perspect Med 5: |
| Mogami, Haruta; Keller, Patrick W; Shi, Haolin et al. (2014) Effect of thrombin on human amnion mesenchymal cells, mouse fetal membranes, and preterm birth. J Biol Chem 289:13295-307 |
Showing the most recent 10 out of 55 publications
