Preterm birth (6 births globally each year, is a major cause of death within the first month of postnatal life. The highest rates of preterm birth (≥15% of all live births) occur in sub-Saharan Africa, Pakistan and Indonesia. In the U.S., the preterm birth rate remains at ~10% of all live births, overall. However, significant racial disparities in preterm birth rates exist, with the incidence of preterm birth among African-Americans being 50% higher than that of the overall population. Notably, the underlying causes for these racial differences remain unknown. Astonishingly, the modalities used to treat and/or prevent preterm labor have changed little over the past 50 years. This is due, in part, to our incomplete understanding of mechanisms that mediate myometrial quiescence and contractility and the reluctance of pharmaceutical companies to engage in drug discovery in this critical area.
Our research is focused on the mechanisms for maintenance of myometrial quiescence during pregnancy and for the increase in uterine contractility leading to labor. We have observed that myometrial quiescence is controlled primarily by the anti-inflammatory and anti-contractile actions of progesterone (P4) (secreted by the placenta and/or the ovarian corpus luteum, depending upon the species), acting via its nuclear receptor (PR) (Fig. 4). As shown in the upper left, we found that P4/PR exerts anti-inflammatory effects by tethering to NF-κB p65 bound to NF-κB response elements (NF-κBRE) within the promoters of proinflammatory and contractile (CAP) genes (e.g. oxytocin receptor [OXTR], connexin 43 [CX43], cyclooxygenase 2 [COX2]). This stimulates recruitment of corepressors, such as GATAD2B. Similar mechanisms are believed to occur at AP-1 sites upstream of CAP gene promoters, whereby PR interacts with FOS/JUN and recruits corepressors. As shown in the upper right, P4/PR also inhibits NF-κB activation and proinflammatory and contractile gene expression in myometrium by binding to the promoter of the NF-κB inhibitor, IκBα, and enhancing its expression. P4/PR also exerts anti-inflammatory effects in myometrium by binding to the MKP1/DUSP1 promoter to increase its expression and prevent MAPK activation, resulting in the inhibition of NF-κB and AP-1 activity. As shown in the lower panel, P4/PR blocks contractile gene expression by binding to the promoter of the transcriptional repressor, ZEB1, and enhancing its expression. The increased levels of ZEB1 bind to the promoters of contractile genes to inhibit their expression, and activates expression of the microRNA, miR-199a/-214, cluster to inhibit expression of their target, COX-2. ZEB1 also inhibits miR-200 expression, leading to further induction of ZEB1 and ZEB2, as well as STAT5b, causing suppression of 20α-HSD, leading to increased local P4 accumulation.
Parturition in all species is associated with an increased inflammatory response and a decline in PR function within the myometrium. Near term, signals from the fetus (e.g. increased surfactant lipoprotein secretion) and mother (e.g. uterine stretch with increased chemokine production, increased estrogen receptor signaling), cause increased immune cell invasion of the fetal membranes, decidua and myometrium. At preterm, immune cell invasion is stimulated by ascending infection associated with chorioamnionitis, as well as increased uterine stretch in twin or multi-fetal pregnancies. The invading immune cells produce proinflammatory cytokines that cause activation of inflammatory transcription factors, such as NF-κB and AP-1, which promote activation of proinflammatory and CAP gene expression and a decline in PR function, caused by a decrease in coactivators and increased expression of truncated PR isoforms. The decline in PR function results in decreased ZEB1 expression, with increased expression of CAP genes and miR-200 family members and decreased expression of the miR-199a/214 cluster. The increase in miR-200s suppress their targets ZEB1/2 and STAT5b and increase local P4 metabolism via upregulation of 20α-HSD. The decrease in miR-199a/214 results in upregulation of their target, COX-2, and an increase in synthesis of contractile prostaglandins. These events culminate in an increase in myometrial contractility leading to parturition.
Studies are ongoing to define the molecular mechanisms whereby key transcriptional coregulators mediate hormonal regulation of myometrial quiescence and contractility, and to identify and characterize novel genes that control myometrial quiescence and contractility.