Regulation of hyaluronan expression during cervical ripening

In preparation for birth, the uterine cervix undergoes a remarkable transformation from a closed, rigid structure to a distensible, remodeled configuration that stretches to allow passage of a fetus. Cervical ripening requires changes in the composition and structure of the extracellular matrix. These include an increase in the glycosaminoglycan hyaluronan (HA) prior to parturition. We show that the increase in cervical HA with advancing gestation correlates with the temporal increase in transcription of hyaluronan synthase 2 (HAS2) in the mouse. On gestation day 18, 1 day prior to birth, HAS2 transcripts are most abundant and begin to decline after birth. The steroid 5alpha-reductase type 1 deficient mouse, which fails to undergo cervical remodeling, has decreased expression of HAS2 mRNA and decreased tissue HA. HAS2 transcripts are expressed by cervical epithelium, and HA is localized to the matrix surrounding the stroma and to a lesser extent around the epithelium. HAS2 expression is suppressed in mice treated with progesterone. The mRNA expression levels of HA metabolizing enzymes hyaluronidase 1 and 2 were unchanged during pregnancy but increased after birth. Thus the net increase in HA content at term correlates with increased transcription of HAS2. Regulation of HA content is conserved in women because HAS2 transcripts are up-regulated in cervices of women in labor as compared to pregnant women not in labor. These results provide insights into the regulation of HA biosynthesis during cervical ripening and underscore the physiological role of HA in this essential process.