Pregnancy in the stroke-prone spontaneously hypertensive rat: investigating impaired vascular remodelling and establishing a novel model of superimposed pre-eclampsia

Hypertensive disorders of pregnancy are an increasingly common disorder in modern society. The increasing prevalence of women with pre-eclampsia superimposed on a background of chronic hypertension is a significant burden in modern society and is profoundly detrimental to both mother and child; during pregnancy and beyond. Little is understood about the development of these multifactorial hypertensive disorders, however there is increasing evidence that the manifestation of hypertensive disorders during pregnancy is not solely due to placental-derived dysfunctions and has important maternally-driven components. The stroke-prone spontaneously hypertensive (SHRSP) rat is a well-established model of human essential hypertension. SHRSP dams remain hypertensive throughout pregnancy and demonstrate an abnormal uterine artery structure and function at term. This project aimed to more fully characterise pregnancy in the SHRSP rat. The objectives were to assess maternal responses and determine how maternal hypertension impacts maternal and fetal well-being as well as placental development; to investigate the underlying genetic mechanisms behind the eventual abnormal pregnancy-dependent uterine artery remodelling; and, finally, to increase the maternal cardiovascular load in SHRSP pregnancy to establish a model of superimposed pre-eclampsia. In vivo and ex vivo techniques were used to characterise cardiovascular function in the hypertensive SHRSP and normotensive WKY rats during gestation, as well as assess pregnancy outcomes. The SHRSP dams were found to have similar cardiac function compared to WKY, yet there was evidence of impaired systemic vascular structure and function in late gestation and placental abnormalities. Nevertheless, the SHRSP maintained similar litter sizes to WKY and did not demonstrate any major impact on fetal growth. Further similarities between SHRSP and WKY pregnancy were revealed with the assessment of uterine artery function in early gestation. However, using RNA sequencing to elucidate the transcriptomic profiles of the uterine arteries, SHRSP were found to have strikingly different responses to pregnancy at the transcript expression level, compared to WKY. Finally, a model of superimposed pre-eclampsia was established by increasing the cardiovascular stress in the dam using angiotensin II infusion during pregnancy in SHRSP. This model had a significantly higher systolic and diastolic blood pressure than the already hypertensive SHRSP. The pregnancy-dependent increase in cardiac output, observed in SHRSP, was negated by AngII infusion and was reduced in the highest treatment group. These major cardiovascular impairments were observed alongside increased proteinuria and reduced fetal growth; all phenotypes found in severely pre-eclamptic women. This work has provided information on systemic and uterine specific vascular responses to pregnancy in SHRSP and WKY rats alongside detail of underlying transcriptional differences. This study was the first to examine uterine artery gene expression changes during pregnancy. The different transcriptomic profiles of early pregnancy changes in the two strains make this an intriguing model to study maternal-driven vascular remodelling in hypertensive pregnancy. Furthermore, this work demonstrated that increasing the cardiovascular load during pregnancy in SHRSP successfully mimics superimposed pre-eclamptic phenotypes and could be used in the assessment of novel therapeutic strategies. To conclude, the SHRSP has the potential to aid our understanding of human pre-eclamptic conditions, especially when endeavouring to determine the impact of maternally-driven components of hypertensive disorders of pregnancy