Trophoblasts and endothelial cells in pregnancy-associated vascularization
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. ^
Health Sciences, Obstetrics and Gynecology|Health Sciences, Pharmacology|Health Sciences, Immunology
"Trophoblasts and endothelial cells in pregnancy-associated vascularization"
Dissertations and Master's Theses (Campus Access).