The role of hyaluronic acid as a mediator and regulator of cervical ripening

Abstract

During pregnancy, hyaluronic acid (HA) concentration in the human cervix is very low, but increases rapidly at the onset of labour. HA has a high affinity for water molecules and hence can maintain tissue hydration. HA can stimulate collagenase production in rabbit cervix, and also stimulates migration and function of polymorphonuclear leukocytes in the tissues. It is an endogenous regulator of interleukin-1 (IL-1). We hypothesized that HA plays an essential role during cervical ripening. The effect of exogenous application of HA (20 mg) on non-pregnant and pregnant (day 23) rabbit cervices was compared with controls. HA induced cervical ripening in both pregnant and non-pregnant animals, and cervical water content was significantly increased. Tissue collagen was markedly decreased. The localization and distribution of HA and HA receptor CD44 was determined in non-pregnant and pregnant human cervical connective tissue using biotinylated HA binding protein and CD44 monoclonal antibodies. Both were widely distributed in the connective tissues, especially around the blood vessels and cervical glands. The effect of IL-8 (50, 100, 150 and 200 ng/ml) on HA production and hyaluronidase (HAase) activity was investigated in cultures of lower uterine segment collected during elective Caesarean sections. HA production was stimulated in a dose-dependent manner; there was no effect on hyaluronidase activity. HA administration (0.5, 1 and 2 mg/ml) stimulated the activities of collagenase and gelatinase together with IL-8 production in the culture supernatants. Thus HA may play an important role in cervical ripening, being involved in the regulation of cervical tissue water content, collagenolytic enzymes and cytokines.

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

“…Tissue water content is also increased presumably due to the increased expression of aquaporin water channel proteins (Anderson et al 2006) and hydrophilic glycosaminoglycans (ElMaradny et al 1997, Straach et al 2005. Increases in the glycosaminoglycan, hyaluronan, result in disruption of the collagen matrix which, along with tissue growth, facilitates cervical ripening (ElMaradny et al 1997, Straach et al 2005. These differences between softening and ripening which are illustrated in Fig.…”

“…In contrast to our observations with cervical softening, cervical ripening at the end of pregnancy is characterized by increased cell proliferation as well as reduced apoptosis of both the epithelia and the stroma which result in an increased circumference of the cervical lumen . Tissue water content is also increased presumably due to the increased expression of aquaporin water channel proteins (Anderson et al 2006) and hydrophilic glycosaminoglycans (ElMaradny et al 1997, Straach et al 2005. Increases in the glycosaminoglycan, hyaluronan, result in disruption of the collagen matrix which, along with tissue growth, facilitates cervical ripening (ElMaradny et al 1997, Straach et al 2005.…”

Localisation and endocrine control of hyaluronan synthase (HAS) 2, HAS3 and CD44 expression in sheep granulosa cells

“…For example, HAS was detected using immunohistochemistry in pig ovary (Miyake et al 2009), ovine cervix (Perry et al 2012) and uterus (Raheem et al 2013) and human endometrium (Nykopp et al 2010). In addition, the HA receptor (CD44) was immunolocalised in ovine cervix (Perry et al 2010) and uterus (Raheem et al 2013), pig ovary (Miyake et al 2006) and oviduct (Tienthai et al 2003), bovine oocytes, embryos and oviduct (Ulbrich et al 2004;Marei et al 2012;Marei et al 2013), cumulus and mural granulosa (Ohta et al 1999;Marei et al 2012) and cervical cells (El Maradny et al 1997). …”

Regulation and roles of the hyaluronan system in mammalian reproduction

“…Hyaluronan content of cervix increases markedly during late pregnancy in human, sheep, guinea pig, rabbit and rat (Downing & Sherwood 1986, Anderson et al 1991, Rajabi et al 1992, El Maradny et al 1997. The HA level increases from 19% of total GAG in early pregnancy to 71% at term (Akgul et al 2012) and the majority of cervical HA in mice is synthesised by HAS2 (Akgul et al 2014).…”