Date of Award
2010
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Pharmacology and Toxicology
Abstract
Dysregulated uteroplacental interaction and vascular remodeling are thought to be associated with the molecular events in preeclampsia. Due to the co-onset of maternal symptoms and placental pathology, we hypothesize that serum from preeclampsia patients could provide a "blueprint" of etiologic factors. To substantiate the hypothesis, a novel three dimensional dual cell culture in vitro model, a mimic of the vascular remodeling events during pregnancy, was established. In this model, unlike term trophoblasts, first trimester trophoblasts engage in a dynamic cross-talk and synchronize with the endothelial cells in a capillary network. Mechanistic studies indicate that poor expression of VEGF C and VEGF receptors coupled with high E-cadherin expression by term trophoblasts contributed to their restricted interactive and migratory properties. Importantly, preeclampsia serum disrupted the cross-talk between trophoblasts and endothelial cells in the endovascular activity that could be traced back to first trimester and second trimester serum samples in a longitudinal study. Moreover, unlike normal pregnancy serum, a single administration of preeclampsia serum in pregnant IL-10 null mice induced full spectrum of preeclampsia-like symptoms. Wild type mice experienced milder pathology. Preeclampsia serum was found to induce hypoxic injury in utero-placental units of IL-10-/- mice, a possible cause for production of sFlt-1 and sEng. Moreover, taking advantage of the in vitro model system, the mechanism(s) that program pregnancy compatible immunovascular role of uterine NK cells that uniquely populate the maternal-fetal interface was delineated. In summary, the findings establish well defined in vivo and in vitro models that offer avenues for understanding the cellular interactions that occur at maternal-fetal interface and delineate the pathogenetic pathways for preeclampsia with a potential for predicting the disorder.
Recommended Citation
Kalkunte, Satyan, "Trophoblasts and endothelial cells in pregnancy-associated vascularization" (2010). Open Access Dissertations. Paper 2347.
https://digitalcommons.uri.edu/oa_diss/2347
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Comments
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