title: Deciphering the vascular disease mechanisms underlying hypertensive disorders of pregnancy
Creators: name: Scott, Kayley
Publisher: name: University of Glasgow
Year: 2023

description: Summary. As the prevalence of hypertensive orders increases, particularly pre-eclampsia superimposed on a background of chronic hypertension (SPE), so too does the global disease burden they represent. Not only are these disorders detrimental to both mother and child during the course of pregnancy, they also have lasting longterm effects to future cardiovascular health for both. Despite this, relatively little is known about the generation and development of these multifactorial disorders. In combination with the effects of potential treatments to offspring health, the resultant scope for therapeutic interventions is severely limited. The stroke-prone spontaneously hypertensive (SHRSP) rat is an established model of chronic hypertension during pregnancy that can be further stressed by infusion of angiotensin II (ANGII) in mid-gestation to create a pre-eclamptic phenotype that closely mimics the clinical manifestation of SPE in humans. This thesis aimed to optimise and characterise a novel rodent model of SPE to provide a useful tool in understanding the underlying pathophysiology of the condition and in testing potential therapeutic strategies. The objectives were to assess the maternal, fetoplacental and neonatal response to SPE development in the SHRSP; evaluate the use of magnesium sulphate (MgSO4) as a preventative therapeutic in the context of SPE; investigate the underlying genetic mechanisms that may influence abnormal uterine artery remodelling due to maternal hypertension; and, finally, to validate these genetic mechanisms in vitro. A variety of in vivo and ex vivo techniques were employed in the generation and assessment of the optimised SPE rodent model. Pregnant SHRSP dams infused with 750ng/kg/min ANGII were found to exhibit signs of impaired maternal cardiovascular, renal and placental function alongside the abnormal uterine artery remodelling already characteristic of the SHRSP. Further, the offspring of these dams were more likely to be growth restricted and preliminary evidence suggested neonatal gene expression may be altered. When MgSO4 was administered in a preventative capacity in daily drinking water, it was shown to improve maternal blood pressure, proteinuria and weight. However, MgSO4 was ineffective at improving maternal cardiac function or uteroplacental flow and was observed to worsen fetal growth restriction. To better understand the maternally-derived factors in this impaired uterine artery remodelling associated with hypertensive pregnancy, RNA-sequencing was used to assess the genetic profiles of early pregnancy uterine arteries in SHRSP and normotensive WKY. Though the two strains shared a conserved response to pregnancy, there were striking differences in pathways related to vascular function, notably reactive oxygen species (ROS) production and calcium (Ca2+) signalling. Finally, using a combination of whole uterine arteries and vascular smooth muscle cells (UAVSMCs) derived from them, the gene expression patterns relating to ROS and Ca2+ were investigated to validate them. Though studies were preliminary and sample sizes small, there was evidence of altered ROS production, NOX subunit expression and UAVSMC Ca2+ release between WKY and SHRSP. This work has provided information on an optimised, novel rodent model of superimposed pre-eclampsia that may be used as a potential tool in investigating the pathophysiology of the condition or in assessing the long-term consequences of an adverse in utero environment. It has also deepened our understanding of the effects of prolonged MgSO4 exposure during pregnancy and highlighted the need for an optimised, standardised dosing regime in humans. Furthermore, this work has generated novel insights into the genetic factors that influence uterine artery remodelling and their functional consequences in early hypertensive pregnancy.