Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.551563
Title: The role of the anti-angiogenic protein, AS4.5, in the pathophysiology of IUGR
Author: Atkinson, Sarah Denise
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2010
Availability of Full Text:
Access through EThOS:
Abstract:
Intrauterine growth restriction (IUGR) contributes significantly to neonatal mortality and morbidity, as well as increased incidence of severe adult disease, being characterised by an estimated fetal weight below the 10th percentile for gestational weight and an abdominal circumference below the 2.5th percentile. Fetal wellbeing is critically dependent on adequate development of placental villi as well as the maternal and fetal vasculatures and in approximately 60% of cases of pure IUGR (those not associated with pre-eclampsia), excessive perivillous fibrinoid material has been associated with poor villous growth. In the present study we used stereological analysis to analyse villous components and found decreased stem, intermediate and terminal villi as well as a reduced intervillous space in placenta from IUGR compared with controls, confirming analyses performed in previous studies. As the fibrinolytic pathway is hyper-activated in IUGR, we hypothesised that anqiostatiru, (AS4.5: an anti-angiogenic 52kDa proteolytic cleavage product of plasminogen), a potent endothelial apoptosis inducing agent produced during fibrinolysis may be involved in the pathophysiology of IUGR. We describe for the first time, that in addition to its' known effects on endothelial cells (which we confirmed), AS4.5 also induces dose-dependent apoptosis in 2 trophoblast cell lines and inhibits cell migration and "wound healing" in trophoblast cultures, while having no such effect on tumour cell lines. Although no definitive antibody for detection of AS4.5 exists, we show that conditions within villi from IUGR placental samples are permissive for generation of AS4.5, as co-immunolabelling for B-actin/plasminogen and B-actin/uPAR are both increased in IUGR samples from placental compared with matched controls. This increased propensity for AS4.5 generation on the villi of IUGR placenta correlates with a 2-3 fold increase in the rate of villous apoptosis within placental samples from cases of I UGR. Thus, generation of an endothelial/trophoblast apoptosis-inducing agent occurs at the site where villous turnover is greatest and is known to contribute to the pathophysiology of IUGR. Taken together, these data support the hypothesis that cell surface generated AS4.5 may contribute to the increased apoptosis observed during thrombophilic- type IUGR and warrants further investigation of placental and serum AS4.5 in a larger cohort of pure I UGR cases as a direct contributor to the pathogenesis of IUGR.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.551563  DOI: Not available
Share: