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.

Public Health Relevance

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-Z)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
United States
Zip Code
Akgul, Yucel; Word, R Ann; Ensign, Laura M et al. (2014) Hyaluronan in cervical epithelia protects against infection-mediated preterm birth. J Clin Invest 124:5481-9
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
Kishore, A Hari; Owens, David; Word, R Ann (2014) Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor-mediated cervical cell-specific mechanisms. J Clin Endocrinol Metab 99:1006-18
Montalbano, Alina P; Hawgood, Samuel; Mendelson, Carole R (2013) Mice deficient in surfactant protein A (SP-A) and SP-D or in TLR2 manifest delayed parturition and decreased expression of inflammatory and contractile genes. Endocrinology 154:483-98
Mendelson, Carole R (2013) GRTH: a key to understanding androgen-mediated germ cell signaling. Endocrinology 154:1967-9
Lindqvist, Annika; Manders, Dustin; Word, R Ann (2013) The impact of reference gene selection in quantification of gene expression levels in guinea pig cervical tissues and cells. BMC Res Notes 6:34
Mogami, Haruta; Kishore, Annavarapu Hari; Shi, Haolin et al. (2013) Fetal fibronectin signaling induces matrix metalloproteases and cyclooxygenase-2 (COX-2) in amnion cells and preterm birth in mice. J Biol Chem 288:1953-66
Rosenfeld, Charles R; DeSpain, Kevin; Word, R Ann et al. (2012) Differential sensitivity to angiotensin II and norepinephrine in human uterine arteries. J Clin Endocrinol Metab 97:138-47
Rosa, Renata Giardini; Akgul, Yucel; Joazeiro, Paulo Pinto et al. (2012) Changes of large molecular weight hyaluronan and versican in the mouse pubic symphysis through pregnancy. Biol Reprod 86:44
Itoh, Hiroko; Kishore, Annavarapu Hari; Lindqvist, Annika et al. (2012) Transforming growth factor ýý1 (TGFýý1) and progesterone regulate matrix metalloproteinases (MMP) in human endometrial stromal cells. J Clin Endocrinol Metab 97:E888-97

Showing the most recent 10 out of 34 publications