Mechanisms by which steroid hormones modulate cervical extracellular matrix structure and function during pregnancy and provide therapeutic protection against preterm birth

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ABSTRACT On an annual basis 3.3 million babies will die worldwide due to complications in pregnancy that leads to preterm birth (PTB) or stillbirths. Despite much investigation, the current understanding of the mechanisms of term and preterm parturition remains limited, the identification of risk factors is incomplete, and preventative therapies are few. Supplemental progesterone (P) therapy in women with a singleton pregnancy and a previous history of PTB is currently the standard of care to prevent PTB in the United States. Yet, our mechanistic understanding of its mode of action is absent. Cervical remodeling, the process by which the cervix transforms from a closed rigid structure to a compliant structure that can open to allow safe passage of the fetus, is a key and essential feature of normal parturition. In human and mice, this process begins in early pregnancy. Thus improved understanding of this mechanism has the potential to inform new early preventative therapies and provide mechanistic insight into current therapies. Based on novel findings in mice lacking the proteoglycan, decorin, we provide evidence that 1) a dysfunctional cervical extracellular matrix (ECM) leads to cervical insufficiency, 2) cervical mechanical dysfunction results from defects in both collagen and elastic fiber assembly and 3) structural organization of the cervical ECM in pregnancy is under exquisite control by progesterone and estrogen. The goal of the current study is to identify the P and E regulated transcriptional networks that regulate ECM structure, protein turnover and mechanical function and to explore the mechanism by which decorin ensures cervical competency in the nonpregnant and early pregnant cervix. Finally we will use mice deficient in the proteoglycans decorin and biglycan to test the hypothesis that P supplementation can repair mechanical function of the cervix and thus provide one mechanism by which P supplementation is beneficial in reducing risk of PTB in women with a previous PTB. Collectively the proposed studies, based on compelling preliminary data, has the potential to both expand our understanding of basic mechanisms in parturition as well as expand the possibilities for clinical intervention in PTB.