Regulation and Function of Hyaluronan in Cervical Remodeling

Ut Southwestern Medical Center, Dallas TX

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Abstract

Preterm birth occurs in 12.5% of pregnancies, affects 500,000 children per year in the United States and has a financial toll that exceeds $26 billion per year. A greater understanding of the molecular processes that regulate parturition are essential for prevention of prematurity. Towards this end our research is aimed at understanding how the cervix remodels in preparation for birth. One unique aspect of cervical ripening and dilation at the end of pregnancy is the marked increase in expression of hyaluronan synthase 2 resulting in increased hyaluronan (HA) production. We propose that hyaluronan has multiple roles in the cervix that are dependent on the HA size, structure, binding partners and cell type. In the current study we will test the hypothesis that high molecular weight HA has important functions during ripening to increase tissue viscoelasticity and that the breakdown to low molecular weight HA serves two functions: 1) to allow loss of tissue integrity and maximal tissue compliance with onset of uterine contraction and 2) to modulate inflammatory events needed for postpartum tissue repair. These functions of HA in cervical remodeling will be tested in mice with a cervix specific depletion of Has2. Temporal changes in hyaluronidase activity will be measured in the mouse and guinea pig cervix during cervical ripening, in labor and postpartum and correlated with changes in biomechanical properties of the cervix as well as migration, activation and phenotype of inflammatory cells before, during and after birth. The interaction of HA with CD44 and toll like receptors and activation of downstream signaling pathways will be evaluated in both macrophage and cervical epithelial cell lines and compared to pathways induced by lipopolysacharide (LPS). The ability of HA to compete with LPS and reduce rates of infection-mediated PTB will be tested in wild type, CD44-/- and TLR4-/- mice. Finally investigations will be carried out using cervical mucus from pregnant women to determine if increased hyaluronidase activity and low molecular weight HA correlates with progression of pregnancy and degree of cervical ripening as determined by a Bishops score. Taken together, these studies will enhance our understanding of the physiological process of cervical remodeling, provide insight into how a matrix molecule can modulate processes important in distinct phases of cervical remodeling before and after birth and will provide the basis for future studies aimed at development of therapies for prevention of complications associated with both preterm and postterm birth.