Dynamic Changes in Cervical Glycosaminoglycan Composition during Normal Pregnancy and Preterm Birth

Abstract

Glycosaminoglycans (GAG) have diverse functions that regulate macromolecular assembly in the extracellular matrix. During pregnancy, the rigid cervix transforms to a pliable structure to allow birth. Quantitative assessment of cervical GAG is a prerequisite to identify GAG functions in term and preterm birth. In the current study, total GAG levels increased at term, yet the abundance, chain length, and sulfation levels of sulfated GAG remained constant. The increase in total GAG resulted exclusively from an increase in hyaluronan (HA). HA can form large structures that promote increased viscosity, hydration, and matrix disorganization as well as small structures that have roles in inflammation. HA levels increased from 19% of total GAG in early pregnancy to 71% at term. Activity of the HA-metabolizing enzyme, hyaluronidase, increased in labor, resulting in metabolism of large to small HA. Similar to mice, HA transitions from high to low molecular weight in term human cervix. Mouse preterm models were also characterized by an increase in HA resulting from differential expression of the HA synthase (Has) genes, with increased Has1 in preterm in contrast to Has2 induction at term. The Has2 gene but not Has1 is regulated in part by estrogen. These studies identify a shift in sulfated GAG dominance in the early pregnant cervix to HA dominance in term and preterm ripening. Increased HA synthesis along with hyaluronidase-induced changes in HA size in mice and women suggest diverse contributions of HA to macromolecular changes in the extracellular matrix, resulting in loss of tensile strength during parturition.

Hyaluronan in cervical epithelia protects against infection-mediated preterm birth

“…During physiologic pregnancy and preterm labor in women and mice, HA levels increase significantly in the cervix (6)(7)(8)(9)(10). HA is synthesized by cervical fibroblasts, epithelial cells, and immune cells and released into the extracellular matrix (ECM) and cervicovaginal mucus.…”

“…At the end of pregnancy, increased expression of the HA synthase 2 (Has2) gene, and consequent increases in epithelial and stromal HA, correlate with maximal cervical distensibility, collagen disorganization, and hydration of the cervix (10). In mice, HA at term pregnancy accounts for 1% of the dry cervical mass, a 5-fold increase compared with early pregnancy (9). Cervical HA is also increased in mouse models of infection-mediated and non-infection-mediated PTB, although expression is limited to the stromal matrix (9).…”

“…In mice, HA at term pregnancy accounts for 1% of the dry cervical mass, a 5-fold increase compared with early pregnancy (9). Cervical HA is also increased in mouse models of infection-mediated and non-infection-mediated PTB, although expression is limited to the stromal matrix (9). In addition to its structural role in the ECM, HA has diverse functions -such as cell growth, migration, adhesion, and differentiationthat are dependent on HA size and expression of HA-interacting molecules such as CD44, versican, and inter-alpha-trypsin inhibitor (12).…”

A compact fiber-optic SHG scanning endomicroscope and its application to visualize cervical remodeling during pregnancy

“…Collagen is the main structural protein in the cervix. Animal studies reveal rearrangement of collagen structure is achieved in part by a decline in collagen crosslink formation, a reduction in matricellular proteins that regulate collagen fibrillogenesis, and increased synthesis of the matrix disorganizing molecule, hyaluronan (3,4). Evidence to support a conservation of these processes in cervical remodeling in women is mounting (5).…”

Composition and significance of glycosaminoglycans in the uterus and placenta of mammals

“…This characteristic was co-related to the increase of the gene HAS2 transcription, positively affected by estrogen which, close to birth, is rather high. Increased HA synthesis and changes induced by hyaluronidase trigger alterations in the macromolecules of the extracellular matrix, with loss of traction resistance in birth (Akgul et al 2012). …”