Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice

Abstract

Cervical remodeling during pregnancy and parturition is a single progressive process that can be loosely divided into four overlapping phases termed softening, ripening, dilation/labor, and post partum repair. Elucidating the molecular mechanisms that facilitate all phases of cervical remodeling is critical for an understanding of parturition and for identifying processes that are misregulated in preterm labor, a significant cause of perinatal morbidity. In the present study, biomechanical measurements indicate that softening was initiated between gestation days 10 and 12 of mouse pregnancy, and in contrast to cervical ripening on day 18, the softened cervix maintains tissue strength. Although preceded by increased collagen solubility, cervical softening is not characterized by significant increases in cell proliferation, tissue hydration or changes in the distribution of inflammatory cells. Gene expression studies reveal a potentially important role of cervical epithelia during softening and ripening in maintenance of an immunomucosal barrier that protects the stromal compartment during matrix remodeling. Expression of two genes involved in repair and protection of the epithelial permeability barrier in the gut (trefoil factor 1) and skin (serine protease inhibitor Kazal type 5) were increased during softening and/or ripening. Another gene whose function remains to be elucidated, purkinje cell protein 4, declines in expression as remodeling progressed. Collectively, these results indicate that cervical softening during pregnancy is a unique phase of the tissue remodeling process characterized by increased collagen solubility, maintenance of tissue strength, and upregulation of genes involved in mucosal protection.

Cervical remodeling in term and preterm birth: insights from an animal model

“…The uppermost region of the endocervix is lined with columnar epithelia, and this squamocolumnar junction delineates the boundary between uterine and cervical tissue. Resident immune cells including neutrophils, eosinophils, and macrophages are present in the cervix though their localization and relative numbers change over the course of pregnancy (Timmons & Mahendroo 2006, Read et al 2007). All these cell types have specific functions during pregnancy and parturition that are in part regulated by the steroid hormone environment.…”

“…Since that time, research by many investigators has confirmed that cervical remodeling is a dynamic process that begins long before the onset of uterine contractions. The cervical remodeling process can be divided into four overlapping phases termed softening, ripening, dilation, and postpartum repair (Read et al 2007). …”

“…Cervical softening is defined as the first measurable increase in tissue distensibility when compared with the nonpregnant cervix and occurs by gestation day 12 in the mouse and rat (Harkness & Harkness 1959, Read et al 2007. Once initiated, there is a slow incremental decline in the tissue stiffness that is maximal at the time of birth (Mahendroo et al 1999, Word et al 2005.…”

“…Previous studies on the murine pregnant cervix documented an increase in collagen solubility during cervical softening with no change in total collagen content. This suggested the potential for regulated alterations in collagen processing during cervical softening (Read et al 2007). While collagen solubility is an indirect indicator of collagen structure, evidence to support downregulation of specific steps in the collagen-processing pathway is mounting (Fig.…”

“…Epithelial functions include immunoprotection and maintenance of a barrier, which are likely important in the protection of the stromal compartment as the matrix remodels. During softening, these functions are exemplified by localization of immune cells to the epithelial/subepithelial regions of the cervix as well as the induction of proteins involved in restitution and repair of the cervical mucosal epithelia (Read et al 2007). These include trefoil factor 1 (TFF1) and serine protease inhibitor Kazal type 5 (SPINK5).…”