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Title: The role of asymmetric dimethylarginine in murine pregnancy and its link to pregnancy-induced hypertension
Author: Georgopoulou, Aikaterini
ISNI:       0000 0004 7969 8949
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Globally, preeclampsia accounts for approximately 10% of pregnancy-related deaths. In the United States, the incidence of the disease has risen dramatically over the last two decades. Pharmacological interventions for the management of preeclampsia are very limited; premature delivery is the only option, often resulting in life-long disabilities. Association studies indicate increased levels of asymmetric dimethylarginine (ADMA) in preeclamptic patients, prior to clinical manifestation. ADMA is a negative regulator of the nitric oxide signaling pathway with high levels leading to systemic hypertension in vivo. Inhibition of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) leads to accumulation of ADMA, suggesting that the latter is actively metabolized by DDAH. We sought to assess the impact of elevated ADMA levels on haemodynamic adaptations during pregnancy and fetoplacental development in vivo through genetic DDAH1 manipulation. Clinical studies have shown that paternal genes increase preeclampsia susceptibility. We hypothesised that a systemic increase in maternal AMDA would lead to a hypertensive response during gestation, mediated by the fetus. In order to test the above hypothesis, two distinct mouse models were generated; a DDAH1 null model and a fetal-specific DDAH1 knockout model. DDAH1 deletion led to accumulation of plasma ADMA, sFlt-1 and sEng during late gestation accompanied by a significant increase in systemic blood pressure. Fetal-specific DDAH1 deletion led to a small but significant increase in maternal circulating ADMA and elevated blood pressure around parturition. Given the above findings, we hypothesized that paternally- inherited single nucleotide polymorphisms (SNPs) with the ddah1 locus might alter the susceptibility to preeclampsia. To test this hypothesis, the frequency of several SNPs was estimated and compared between babies from preeclamptic and normotensive pregnancies. No correlation was identified for any of the variants analysed, suggesting that paternal DDAH1 does not alter the risk of preeclampsia. It is worth mentioning that the analysis was done in a small cohort; as such, additional studies are needed in order to draw safe conclusions.
Supervisor: Johnson, Mark ; Leiper, James Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral