CHARACTERISING A NOVEL MODEL OF SUPER-IMPOSED PRE-ECLAMPSIA

Abstract

Objective: The stroke-prone spontaneously hypertensive (SHRSP) rat is a model of chronic hypertension and defective vascular remodelling during pregnancy that can be stressed by administration of angiotensin II (ANGII) to mimic super-imposed pre-eclampsia. This novel model has been tested with doses of 500 ng/kg/min and 1000 ng/kg/min ANGII. The aim of this study was to characterise the pathology of this model with a dose of 750 ng/kg/min to enhance reproducibility and refine the model. Design and method: SHRSP and normotensive Wistar Kyoto (WKY) females were time mated with males of the relevant strain. On gestational day (GD) 10.5 mini osmotic pumps were implanted administering either 0.9% saline or 750 ng/kg/min of ANGII. SHRSPs were split into either SHAM (saline) or ANGII groups. WKY received saline only. At pre-pregnancy (PP), GD 6.5, 14.5 and 18.5 blood pressure, cardiac function and uteroplacental blood flow were measured by tail cuff plethysmography and ultrasound. Urine was collected by metabolic cage at PP, GD6.5 & 18.5 to assess proteinuria. Results: ANGII showed reduced pregnancy-related weight gain vs WKY and SHAM (168.3 ± 3.7 g vs 231.2 ± 3.0 g vs 183.3 ± 5.9 g, p < 0.001). ANGII showed an increased BP when compared to SHAM and WKY (180.9 ± 9.7mmHg vs 127.5 ± 6.5mmHg vs 139.8 ± 7.1 mmHg p < 0.001 GD18.5). ANGII dams showed signs of left ventricular cardiac dysfunction with an elevated relative wall thickness and reduced stroke volume and cardiac output vs WKY (p < 0.05). ANGII and SHAM exhibited impaired uteroplacental blood flow vs WKY at GD18.5 (0.57 ± 0.03au vs 0.62 ± 0.05au vs 0.38 ± 0.02au, p < 0.01). Infusion of ANGII successfully induced proteinuria, measured as urinary albumin:creatinine compared to SHAM and WKY (12.2 ± 8.28 μg/μmol/L vs 0.16 ± 0.01 μg/μmol/L vs 3.9 ± 0.40 μg/μmol/L, p < 0.001). Conclusions: The results presented here show this model has effectively captured the overall disease picture of pre-eclampsia with consistent disease characteristics such as proteinuria, hypertension, maternal cardiovascular impairment and dysregulated uterine artery remodelling. It may serve as a useful tool in the study of pre-eclampsia.