Maternal tissue perfusion and altered expression of hypoxia regulated genes in pre-eclampsia

Karanam, Vijaya Lakshmi (2017) Maternal tissue perfusion and altered expression of hypoxia regulated genes in pre-eclampsia. (PhD thesis), Kingston University, .


Pre-eclampsia is an enigmatic multisystem disorder of the second half of pregnancy. Placental hypoxia and generalised endothelial dysfunction are features of this syndrome and the clinical manifestations of this disease are suggestive of reduced maternal tissue perfusion. There is convincing evidence that the hypoxic placenta released as yet unknown circulating factor(s), which rsult in the generalised endothelial dysfunction. The hypothesis of this study is that, altered expression of hypoxia regulated genes occurs in the placenta and vascular endothelium in pregnancies complicated by pre-eclampsia which accounts for the clinical manifestations of the syndrome including the reduced blood flow. There is an ongoing debate regarding the shared and disparate components of the pathophysiology of pre-eclampsia and Intra uterine growth restriction (IUGR) hence women with IUGR pregnancy were also included in this study. The primary aim of this research was to identify, through bioinformatics a set of hypoxia regulated genes in pre-eclamptic placenta and then to validate the results through RT-qPCR from the placenta and also in edothelial cells exposed to the plasma from three groups of women (pre-eclampsia, IUGR and normal pregnancy) recruited for the study. First, Strain gauge plethysmography was used to measure maternal tissue blood flow in the claf, which was compared to tissue oxygen saturation measured using pulse oximetry in the three groups of women. Second, using bioinformatics, a set of novel potential hypoxia regulated genes namely angiogenein inhibitor, apolipoprotein E, growth differentiating factor (GDF15), HS19, KISS1, NAD-Ubiquinone oxidoreductase 1 (NDUFAB1) and ROBO$ were identified and RT-qPCR was used to study their expression in the placenta and also in the two endothelial cell lines, (Human umbilical vein endothelial cells and Myometrial uterine microvascular endothelial cells) exposed to hypoxic conditions and plasma from the threee groups of women. Calf blood flow was significantly decreased in women with pre-eclampsia however the difference was not statistically significant in women with IUGR pregnancy compared to normal pregnancy. Notably, tissue oxygen saturation was not significantly different between the three groups of women and there was no correlation between tissue blood flow and oxygen saturation in all the three groups. Overall, the expression of the novel hypoxia regulated genes was increased in pre-eclamptic placenta compared to placenta from normal pregnancy. There was an overall reduction in the expression of the hypoxia regulated genes by HUVEC exposed to plasma from women with pathological pregnancies. However there was no change in expression of the hypoxia regulated genes by UtMVEC when exposed to similar conditions. The study findings suggest that in pre-eclampsia there is compensatory up-regulation of hypoxia regulated genes in the placenta probably in response to uteroplacental ischemia. In both pre-eclampsia and IUGR, there is a failure of up- regulation of hypoxia regulated genes in maternal endothelial cells cultured in vivo in response to circulating factor(s) released by the hypoxic placenta and this may explain the clinical manifestation of impaired tissue perfusion.

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