A dynamical systems model of progesterone receptor interactions with inflammation in human parturition

Abstract

BackgroundProgesterone promotes uterine relaxation and is essential for the maintenance of pregnancy. Withdrawal of progesterone activity and increased inflammation within the uterine tissues are key triggers for parturition. Progesterone actions in myometrial cells are mediated by two progesterone receptor (PR) isoforms, PR-A and PR-B, that function as ligand-activated transcription factors. PR-B mediates relaxatory actions of progesterone, in part, by decreasing myometrial cell responsiveness to pro-inflammatory stimuli. These same pro-inflammatory stimuli promote the expression of PR-A which inhibits the anti-inflammatory activity of PR-B. Competitive interaction between the progesterone receptors then augments myometrial responsiveness to pro-inflammatory stimuli. The interaction between PR-B transcriptional activity and inflammation in the pregnancy myometrium is examined using a dynamical systems model in which quiescence and labor are represented as phase-space equilibrium points. Our model shows that PR-B transcriptional activity and the inflammatory load determine the stability of the quiescent and laboring phenotypes. The model is tested using published transcriptome datasets describing the mRNA abundances in the myometrium before and after the onset of labor at term. Surrogate transcripts were selected to reflect PR-B transcriptional activity and inflammation status.ResultsThe model coupling PR-B activity and inflammation predicts contractile status (i.e., laboring or quiescent) with high precision and recall and outperforms uncoupled single and two-gene classifiers. Linear stability analysis shows that phase space bifurcations exist in our model that may reflect the phenotypic states of the pregnancy uterus. The model describes a possible tipping point for the transition of the quiescent to the contractile laboring phenotype.ConclusionsOur model describes the functional interaction between the PR-A:PR-B hypothesis and tissue level inflammation in the pregnancy uterus and is a first step in more sophisticated dynamical systems modeling of human partition. The model explains observed biochemical dynamics and as such will be useful for the development of a range of systems-based models using emerging data to predict preterm birth and identify strategies for its prevention.

Myometrial Transcriptional Signatures of Human Parturition

“…Further research in this area will help identify the timing mechanisms and responsible pathways for transitioning the quiescent myometrium to the contractile state, which involves many factors and processes (inflammatory load, functional progesterone withdrawal, tissue cross-talk) working in concert (Menon et al, 2016). Understanding these timing mechanisms and the relationship between progesterone and inflammation can then be used to model parturition and make predictions about preterm birth risk (Brubaker et al, 2016). Larger studies probing gene expression throughout pregnancy and labor in humans is much more difficult, however, steps in this direction would improve our understanding of how the uterine tissues establish and maintain quiescence, prepare for labor, and achieve parturition.…”

Exosomes Cause Preterm Birth in Mice: Evidence for Paracrine Signaling in Pregnancy

“…These exosomes likely override proposed immunosuppressive effects of progesterone in the cervix and the uterus. In a related study, exosomes from oxidative stress-induced human amnion epithelial cells caused functional progesterone withdrawal (progesterone receptor [PR]A:PRB ratio switch) in human myometrial cells, which is a theorized mechanism associated with human labor 74–76 . Therefore, the possibility that exosomes may also cause endocrine disruption to ensure labor and delivery cannot be excluded.…”

Developing a theoretical evolutionary framework to solve the mystery of parturition initiation

“…This model posits that a combination of restraining and promoting signals leads to parturition when a crossover threshold is reached for dominant labor-promoting actions, as suggested in a more specific manner for the relationship of P4 and inflammation signals ( Brubaker et al, 2016 ). This model also suggests that the gestation clock, parturition block and parturition stimulatory models co-exist as part of a complementary, overlapping, and fail-safe system to control birth timing.…”