Remodeling of the Cervix and Parturition in Mice Lacking the Progesterone Receptor B Isoform

Yellon, Steven M.; Oshiro, Bryan T.; Chhaya, Tejas; Lechuga, Thomas J.; Dias, Rejane M.; Burns, Alexandra E.; Force, Lindsey; Apostolakis, Ede Marie

doi:10.1095/biolreprod.111.091983

Cited by 30 publications

(47 citation statements)

References 44 publications

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“…Cervix were rehydrated in phosphate buffered saline, a graded series of alcohols, then embedded in paraffin and sectioned at 10 μm. As previously shown, 13,26 longitudinal sections of cervix from each mouse were stained with picrosirius red to assess collagen content and cross-linked structure. Photomicrographs of birefringence of transmitted polarized light in sections were taken (Zeiss AxioImager A1, 20× objective).…”

Section: Methodsmentioning

confidence: 99%

Prevention of preterm birth by progestational agents: what are the molecular mechanisms?

Nold¹,

Maubert²,

Anton³

et al. 2013

American Journal of Obstetrics and Gynecology

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OBJECTIVE Clinically, vaginal progesterone (VP) and 17 alpha-hydroxyprogestreone caproate (17P) have been shown to prevent preterm birth (PTB) in high risk populations. We hypothesize treatment with these agents may prevent PTB by altering molecular pathways involved in uterine contractility or cervical remodeling. STUDY DESIGN Using a mouse model, on days E14-E17 CD-1 pregnant mice were treated with either 1) 0.1cc of 25 mg/ml of 17P subcutaneously, 2) 0.1cc of castor oil subcutaneously, 3) 0.1 cc of 10 mg/ml of progesterone in Replens vaginally, or 4) 0.1cc of Replens vaginally, with four dams per treatment group. Mice were sacrificed six hours after treatment on E17.5. Cervices and uteri were collected for molecular analysis. RESULTS Exposure to VP significantly increased the expression of Defensin 1 compared to Replens (p<0.01) on E17.5. Neither VP nor 17P altered the expression of uterine contraction-associated proteins, progesterone mediated regulators of uterine quiescence, microRNAs involved in uterine contractility, or pathways involved in cervical remodeling. In addition, neither agent had an effect on immune cell trafficking or collagen content in the cervix. CONCLUSION Neither VP nor 17P had any effect on the studied pathways known to be involved in uterine contractility or quiescence. In the cervix, neither VP nor 17P altered pathways demonstrated to be involved in cervical remodeling. Administration of VP was noted to increase the expression of the antimicrobial protein Defensin 1. Whether this molecular change from VP results in a functional effect and is a key mechanism by which VP prevents PTB requires further study.

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Section: Methodsmentioning

confidence: 99%

Prevention of preterm birth by progestational agents: what are the molecular mechanisms?

Nold¹,

Maubert²,

Anton³

et al. 2013

American Journal of Obstetrics and Gynecology

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“…For other polymorphonuclear leukocytes, neutrophils in particular, their increased presence in peripartum vs. non-pregnant cervix of women suggested a role in the ripening process and degradation of the extracellular collagen matrix (72,(91)(92)(93). Further study has not supported this conclusion because a greater census of neutrophils in the cervix occurs only near labor or after degradation of collagen becomes evident in women and rodents (39,81,84,(94)(95)(96). For eosinophils, there are more than a few similarities in morphology and functions for this immune cell in humans and mice (97).…”

Section: Ripeningmentioning

confidence: 98%

“…A comprehensive review of immune cells at the internal fetal-maternal interface in humans and rodents recognized inflammation as a central component of the mechanism of labor (42). Though less information is available for the external fetal maternal interface that involves the cervix, evidence clearly indicates increase in presence of macrophages in the cervix before the day of birth in rodents (83)(84)(85)87). However, further study in mice during the transition from a soft to ripening cervix now indicates inflammation occurs earlier, between day 15-17 of pregnancy, with respect to reduced densities of cell nuclei and cross-linked collagen and greater abundance of resident macrophages with proinflammatory phenotypes (Figure 2).…”

Section: Ripeningmentioning

confidence: 99%

“…Sparse distribution of PR cells in the luminal epithelium notwithstanding, there is little evidence to suggest resident macrophages or other cells have PR. Moreover, only the PR-A, not PR-B isoform is necessary to mediate effects of progesterone for all reproductive functions (84,118). In the absence of information about membrane PR in the cervix, the current concept is that stromal fibroblasts integrate various convergent local factors and systemic influences to mediate progesterone efficacy.…”

Section: Schema For Cervix Transformation From Soft To Ripe To Dilatimentioning

confidence: 99%

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Immunobiology of Cervix Ripening

Yellon

2020

Front. Immunol.

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The cervix is the essential gatekeeper for birth. Incomplete cervix remodeling contributes to problems with delivery at or post-term while preterm birth is a major factor in perinatal morbidity and mortality in newborns. Lack of cervix biopsies from women during the period preceding term or preterm birth have led to use of rodent models to advanced understanding of the mechanism for prepartum cervix remodeling. The critical transition from a soft cervix to a compliant prepartum lower uterine segment has only recently been recognized to occur in various mammalian species when progesterone in circulation is at or near the peak of pregnancy in preparation for birth. In rodents, characterization of ripening resembles an inflammatory process with a temporal coincidence of decreased density of cell nuclei, decline in cross-linked extracellular collagen, and increased presence of macrophages in the cervix. Although a role for inflammation in parturition and cervix remodeling is not a new concept, a comprehensive examination of literature in this review reveals that many conclusions are drawn from comparisons before and after ripening has occurred, not during the process. The present review focuses on essential phenotypes and functions of resident myeloid and possibly other immune cells to bridge the gap with evidence that specific biomarkers may assess the progress of ripening both at term and with preterm birth. Moreover, use of endpoints to determine the effectiveness of various therapeutic approaches to forestall remodeling and reduce risks for preterm birth, or facilitate ripening to promote parturition will improve the postpartum well-being of mothers and newborns. The maternal immune system in mammals adapts to tolerate the differentiation of novel structures associated with the fetal allograft. Development of two interfaces protect the fetus from rejection and assault by the ecology of the external environment. The internal fetal-maternal interface, as represented by the fetal membranes, placenta, and decidua, is crucial for maintaining maternal inflammatory reactivity for surveillance and responses to pathogens. Discussion of the internal interface is elsewhere and in this special volume (1-3). However, the present review is focused on the external fetal-maternal interface consisting of an amniotic fluid buffer, in a forebag region later in pregnancy as the fetal head engages the lower uterus, and the fetal membranes as they press against the internal os of the cervix. This description of a singleton pregnancy in primates near term applies to rodents, despite anatomical differences in the uterus described below, because observations indicate a single fetal sac engages the internal os of the cervix shortly before labor. The success of this external interface to fend off the biome and virome in the vagina reflects the barrier function of the cervix to protect both the fetus and maternal host structures in the uterus. The cervix barrier function has both immunological and structural components. One part of the mate...

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“…65,66 It was noted above that progesterone rises again beginning around the third postpartum day in rats. 165 Unfortunately, nothing has been reported regarding the maternal behaviors of any PRKO females. 161 The opposite result, increased nursing, is found when progesterone is elevated during later lactation, so perhaps the second decline in progesterone starting around day 10 postpartum contributes to the decline in maternal behavior in rats.…”

Section: Laboratory Rodentsmentioning

confidence: 99%

Parenting Behavior

Lonstein

2015

Knobil and Neill's Physiology of Reproduction

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Remodeling of the Cervix and Parturition in Mice Lacking the Progesterone Receptor B Isoform

Cited by 30 publications

References 44 publications

Prevention of preterm birth by progestational agents: what are the molecular mechanisms?

Prevention of preterm birth by progestational agents: what are the molecular mechanisms?

Immunobiology of Cervix Ripening

Parenting Behavior

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