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Title: Preeclampsia link to gestational hypoxia
Author: Tong, Wen
ISNI:       0000 0004 9359 8696
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Pregnancy is a vulnerable period and complications can adversely affect mother and child. Pregnancy disorders, such as preeclampsia, contribute to significant morbidity and mortality worldwide, but underlying mechanisms remain uncertain, preventing effective diagnosis and treatment. Preeclampsia is a placental disorder originating from impaired spiral artery remodelling and resulting in increased placental vascular resistance, reduced uteroplacental perfusion, triggering placental hypoxia and oxidative stress. In turn, placental dysfunction is thought to be a common denominator between upstream adverse effects on the mother and downstream adverse effects on the fetus. Maternal adverse effects include the angiogenic imbalance that promotes maternal endothelial dysfunction, and adverse effects on the offspring include fetal growth restriction, which is not only a major driver of perinatal morbidity, but also increases cardiometabolic risk in later life. In this thesis, we used bespoke isobaric chambers to induce hypoxia in sheep for the last third of pregnancy and adopted an integrative approach, combining experiments in vivo with those at the cellular and subcellular levels to investigate whether we could recapitulate maternal, placental and fetal signatures associated with preeclampsia. The data reveal that hypoxic placentae showed increased oxidative stress, activation of the unfolded protein response, expansion of the endoplasmic reticulum, loss of cristae structure and size in the mitochondria, a shift in mitochondrial respiration away from fatty acid towards glucose metabolism, and increased expression of the anti-inflammatory cytokine tumour necrosis factor α and the anti-angiogenic factors soluble fms-like tyrosine kinase and soluble endoglin. Upstream adverse consequences on the hypoxic ewe included evidence of an angiogenic imbalance in maternal plasma, increased constrictor reactivity in isolated uterine and femoral arteries, impaired glomerular ultrafiltration, increased uterine artery pulsatility and a reduced ontogenic fall in uterine vascular resistance and in arterial blood pressure with advancing gestation. Downstream adverse consequences on the hypoxic fetus included growth restriction with evidence of brain sparing. Combined, therefore, the data show that chronic hypoxia during pregnancy provides a link between placental stress, fetal growth restriction and maternal cardiovascular dysfunction in adverse pregnancy, as in preeclampsia.
Supervisor: Giussani, Dino A. Sponsor: University of Cambridge ; Physiological Society ; Wellcome Trust ; British Heart Foundation ; Biotechnology and Biological Sciences Research Council ; Lister Institute of Preventive Medicine
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Preeclampsia ; Gestational hypoxia ; Fetal growth restriction ; Placental dysfunction ; Animal model