| Summary: | Thesis (Ph.D.)--Memorial University of Newfoundland, 2010. Medicine Includes bibliographical references (leaves 235-272) Preterm labour is the leading cause of perinatal morbidity and mortality in North America and its prevention is essential to improve pregnancy outcomes. Unfortunately, the basic biochemical and molecular mechanisms of myometrial function during pregnancy and labour remain poorly understood making it difficult to anticipate and prevent preterm labour. Focal adhesions are important to properly anchor growing cells to their ECM and it is becoming appreciated that they are reorganized in myometrial cells during pregnancy and labour to facilitate the significant uterine growth seen during this time. Integrins are an important component of focal adhesions. In this thesis, I initially investigated the gestation profile of ITGA5, ITGA1, ITGA3 and ITGB1 in rat myometrium during pregnancy and labour. The gene expression of all 4 integrins was elevated during late pregnancy and the apparent accumulation of all 4 integrin proteins at myocyte membranes may contribute to the cell-ECM interactions required for the development of a mechanical syncytium and the coordinated contractions of labour. Delaying labour, through the administration of progesterone, maintained ITGA5 gene and protein expression. Inducing preterm labour, by administering RU486, a progesterone receptor antagonist, resulted in a slight increase in only ITGA5 expression and its accumulation at myocyte membranes. In a unilateral pregnant rat model, ITGA5 gene and protein expression was increased with gravidity. -- In further experiments, we examined the effect of ITGA5 silencing on fibronectin deposition and secretion by uterine smooth muscle cells, which is important to aid in the development of a fibronectin matrix. We found that silencing ITGA5 gene expression resulted in a decrease in ITGA5 protein expression and decreased fibronectin deposition and secretion in human myometrial cells. Our results support the idea that ITGA5B1 plays an integral part in FN fibrillogenesis in uterine myometrial cells. -- We suggest that these series of experiments support the concept that a mechanical syncytium may develop in the myometrium to facilitate the coordinated contractions of labour. In addition, ITGA5B1 may be required for fibronectin matrix assembly in the myometrium and initiate the process of cellular cohesion, which is dependent on correct cytoskeletal filament organization, focal adhesion formation, cell-cell and cell-ECM interactions and these processes may be components of myometrial activation aiding in the development of a mechanical syncytium.
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