Mechanisms by which the myometrial ECM modulates myometrial cell function

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ABSTRACT Preterm birth is a leading cause of infant mortality and can lead to long term health challenges in survivors. Fifteen million children are born prematurely worldwide on an annual basis. Identification of risk factors and development of preventative therapies against preterm birth require improved understanding of the molecular processes that drive parturition at term. Over the course of pregnancy the uterus grows and remodels to accommodate the growing fetus yet remains quiescent until term when the uterus transforms to a contractile state for successful delivery. Fetal, mechanical, hormonal and inflammatory signals collectively regulate the balance between myometrial quiescence and contractility though our understanding of the molecular details remains incomplete. Increased synthesis of extracellular matrix (ECM) proteins noted in rodents in mid- pregnancy support a role for ECM in regulating mechanical signals that may regulate phenotypic changes in the myometrial cell. The focus of this application is to understand the regulatory role of myometrial ECM structure on myometrial cell phenotype and function in pregnancy. With this goal in mind, we will study the role and regulation of lysyl oxidase (LOX), a key enzyme that targets the ECM components collagen and elastic fibers to regulate the stiffness and strength of the ECM. We provide evidence that 1) LOX expression is temporally induced in the mouse myometrium in the synthetic phase (gestation days12 and 15) of myometrial remodeling; 2) inhibition of LOX activity in pregnancy prevents onset of parturition and prevents the induction of contraction associated genes such as connexin 43, oxytocin receptor and prostaglandin endoperoxide synthase 2. We will determine if LOX regulates structural changes in the ECM and functional changes in the myometrium that result in increased strength of the myometrium during the synthetic phase of remodeling. We will also investigate whether LOX-mediated increases in tissue stiffness provides a mechanical signal that is required to transition myometrial cells from quiescence in the synthetic phase to a contractile cell at term. These studies will broaden our understanding of the mechanical signals that regulate the balance between uterine quiescence and contractility and thus lead to identification of therapeutic targets for prevention of premature uterine contractions and preterm birth. In addition these studies will integrate the varied expertise of the applicant and provide the requisite training and career development required for his successful development of a strong independent research program that will address an important and understudied area of uterine biology.