Preeclampsia is a hypertensive disorder of pregnancy that affects up to 8% of women worldwide. Preeclampsia is one of the main causes of maternal and neonatal deaths and has shown to increase the risk for the development of cardiovascular disease in the offspring later in life. This effect is worsened when preeclampsia takes place on a hypertensive background, known as superimposed preeclampsia. The association between hypertension during pregnancy and the detrimental cardiovascular impact in the offspring remains to be determined. For this reason, the development of an animal model of preeclampsia is needed to understand the deleterious effect throughout the offspring’s lives. The aim of this study was to investigate the cardiovascular impact of a hypertensive in utero environment in the offspring of a rat model of superimposed preeclampsia.

Pregnant stroke-prone spontaneously hypertensive rats (SHRSP) were implanted with an osmotic minipump for the continuous delivery of 0.9% saline (control) or 660-700 ng/kg/min angiotensin II (ANGII) at gestational day 10.5 (n=6/group). Pregnancies progressed until birth and offspring were weighed between 1 and 7 days of age. Echocardiography and systolic blood pressure (SBP) measurements were carried out regularly on the offspring (n=16-19/group) between 5 and 17 weeks of age (W5-17), and tissues were harvested for wire myography at sacrifice (W18-19). Animal procedures were performed according to regulations established in the Animals (Scientific Procedures) Act 1986, under the Home Office approval of Project Licence PP0895181. 

Exposure to ANGII infusion during pregnancy caused significant growth restriction in the offspring (7.2±2.4 (control) v. 5.9±1.6g (ANGII); Welch’s t-test, P=0.003). Regular phenotyping of the offspring between W5 and 17 showed no significant differences in SBP between groups (151.5±24.7 (control) v.  147.2±22.2 mmHg (ANGII); repeated measures two-way ANOVA, P=0.14). In contrast, early indices of increased left ventricular mass index were apparent at 9 weeks of age in the ANGII-exposed offspring (2.0±1.5 (control) v. 3.1±0.5 (ANGII); repeated measures two-way ANOVA, P=0.04), in parallel with an elevated cardiac output compared to the control offspring (40.1±24.6 v. 62.2±16.1ml/min; repeated measures two-way ANOVA, P=0.02), which may be part of a protective mechanism in response to the limited cardiac development in an adverse in utero environment. Evidence of systolic dysfunction in the offspring exposed to ANGII was observed at W17 by a reduction in fractional shortening (53.5±6.9 (control) v. 45.9±6.9% (ANGII); repeated measures two-way ANOVA, P=0.01). In addition, the E/A ratio was increased in the ANGII-exposed offspring between W5-17 (1.52±0.08 (control) v. 1.94±0.1 (ANGII); repeated measures two-way ANOVA, P=0.0006), which is evidence of diastolic dysfunction. Finally, mesenteric arteries from the offspring exposed to in utero ANGII showed a trend towards increased contraction in response to noradrenaline (150.7±83.1 (control) v. 215.8±115.9 mN∙M (ANGII); Welch’s t-test, P=0.08).

In conclusion, the offspring of the pregnant SHRSP females exposed to ANGII present a worsened cardiovascular phenotype compared to controls, evidenced by both systolic and diastolic cardiac dysfunction. The causes of this cardiovascular effect are yet to be elucidated, however, these results allow an exploration of potential links between preeclampsia and the detrimental developmental programming of the offspring.