The Molecular Mechanisms of Cervical Ripening Differ between Term and Preterm Birth

Abstract

In the current study, the mechanisms of premature cervical ripening in murine models of preterm birth resulting from infection or early progesterone withdrawal were compared with the process of term cervical ripening. Tissue morphology, weight, gene expression, and collagen content along with immune cell populations were evaluated. Premature ripening induced by the progesterone receptor antagonist mifepristone results from an acceleration of processes in place during term ripening as well as partial activation of proinflammatory and immunosuppressive processes observed during postpartum repair. In contrast to term or mifepristone-induced preterm ripening, premature ripening induced in an infection model occurs by a distinct mechanism which is dominated by an influx of neutrophils into the cervix, a robust proinflammatory response and increased expression of prostaglandin-cyclooxygenase-endoperoxide synthase 2, important in prostaglandin biosynthesis. Key findings from this study confirm that cervical ripening can be initiated by more than one mechanism and is not necessarily an acceleration of the physiologic process at term. These results will influence current strategies for identifying specific etiologies of preterm birth and developing subsequent therapies.

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

“…This suggests that reduced cross-linking in the cervix during softening plays a role in the reduced mechanical strength of the cervix seen at this time. Equally important in this study was the finding that the ratio of the fibrillar collagens, type I and type III, remains constant throughout pregnancy, and thus alterations in I to III ratio is unlikely to be an important mechanism for the progressive decline in tissue stiffness (Akins et al 2011). Furthermore, collagen turnover appears upregulated throughout pregnancy.…”

“…This evidence includes a decline in cervical expression and/or activity of lysyl hydroxylase and lysyl oxidase (LOX), respectively, early in pregnancy and a subsequent decline in collagen containing the stronger pyridinoline cross-links in the second half of gestation (Ozasa et al 1981, Akins et al 2011. Cross-links between collagen molecules are essential in providing strength to the resulting collagen fibers and tissues (Eyre et al 1984).…”

“…Matricellular proteins are a family of nonstructural proteins that modulate collagen function and cell-matrix interactions (Bornstein & Sage 2002). Genes encoding two members of this family, thrombospondin 2 (Thbs2) and tenascin-C (Tnc), are downregulated early in gestation and remain low until just before birth (Akins et al 2011). Numerous studies including the evaluation of mice deficient in Thbs2 indicate that this matricellular protein plays a role in cervical softening and in the formation of appropriately assembled collagen fibrils, regulates activity of Mmp2, and is an inhibitor of angiogenesis in a variety of tissues (Kyriakides et al 1998, Kokenyesi et al 2004.…”

“…Other experimental findings call this model into question including the observations that 1) collagen synthesis is upregulated during pregnancy, 2) biomechanical properties of cervices treated exogenously with collagenase differ from term ripening, and 3) changes in collagen structure and organization rather than abundance are observed by polarized light microscopy and transmission electron microscopy (Yu et al 1995, Buhimschi et al 2004, Akins et al 2011. Studies on mice and rats indicate that while total collagen content is constant throughout pregnancy and parturition, collagen structure undergoes dynamic changes as determined by second harmonic generation (SHG), electron microscopy, and light-induced fluorescence (Yu et al 1995, Maul et al 2003, Akins et al 2011.…”

“…Studies on mice and rats indicate that while total collagen content is constant throughout pregnancy and parturition, collagen structure undergoes dynamic changes as determined by second harmonic generation (SHG), electron microscopy, and light-induced fluorescence (Yu et al 1995, Maul et al 2003, Akins et al 2011. Collagen ultrastructure as observed in electron micrographs reveals a progressive increase in collagen fibril diameter in the cervix from early to late gestation along with increased spacing between fibrils (Fig.…”