Cervical remodeling during pregnancy and parturition

Abstract

Appropriate and timely cervical remodeling is key for successful birth. Premature cervical opening can result in preterm birth which occurs in 12.5% of pregnancies. Research focused on the mechanisms of term and preterm cervical remodeling is essential to prevent prematurity. This review highlights recent findings that better define molecular processes driving progressive disorganization of the cervical extracellular matrix. This includes studies that redefine the role of immune cells and identify diverse functions of the cervical epithelia and hyaluronan in remodeling. New investigations proposing that infection-induced premature cervical remodeling is distinct from the normal process are presented. Recent advances in our understanding of term and preterm cervical remodeling provide new directions for investigation and compel investigators to reevaluate currently accepted models.

Figure 1

Changes in the Cervical Stroma and Epithelia During the Remodeling Process. (a) Transmission electron microscopy (20,500X) of a cross section of mouse cervical collagen fibrils. These images provide a dramatic illustration of the change in matrix organization from early to late pregnancy that result in maximal loss of cervical tensile strength at birth. On day 6 of gestation (upper), fibrils are smaller and form a tightly packed organized structure. By late on gestation (day 18; lower), the fibrils are slightly larger, most likely due to the loss of collagen cross-linking and changes in matricellular proteins. Packing is disorganized with large spaces between fibrils and the increase in glycosaminoglycans (GAGs) produced at term. This disorganization of the extracellular matrix leads to a loss of tissue integrity allowing the cervix to open during birth. Bar, 1μm. (b) The cervical epithelia play important functions to protect the weakened stromal matrix. To meet these demands, the epithelia (E) proliferate and differentiate through pregnancy. In addition, changes in barrier properties as well as increased expression of repair and surveillance proteins function to protect the cervix (e.g. TFF1 and SPINK5). The increased production of cervical mucus provides both immune and physical protection. Additionally, enzymes upregulated during cervical ripening, such as HAS2 (synthesizes HA) and SRD5a1, are produced in the epithelium. SRD5a1 is required for metabolism of progesterone in the cervix. The loss of progesterone function is a key step in initiating cervical ripening at term. S, Stroma, M, Mucus, Os- cervical opening.

Figure 2

Proposed model for hyaluronan's functions in cervical remodeling. (a) A cartoon representing the stromal cross section from Figure 1a illustrates the increase in high MW hyaluronan (HA) in the stromal matrix from early to late pregnancy. (b) As HA synthesis is increased at the end of pregnancy, we propose it forms cross-links with versican leading to increased tissue compliance, viscoelasticity and collagen disorganization. (c) During labor, hyaluronidase (HAase) and ADAMTS enzymes cleave HA and versican, respectively, causing a complete loss of integrity and cervical dilation. (d) During postpartum repair, low MW HA, versican fragments and damaged collagen must be removed with the help of immune cells such as neutrophils (Neu) and macrophages (MΦ).