Abstract
Women with Preeclampsia (PE), a form of new onset hypertension during pregnancy, exhibit alterations in the renin angiotension system (RAS). These differences include angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA), ANG II sensitivity, and increased oxidation and levels of angiotensinogen (AGT). While antihypertensive drugs are used in pregnancy, their use is associated with reduced fetal growth, and RAS blockade is specifically contraindicated due to fetotoxicity. AGT is the precursor to ANG II and the initial substrate of the RAS pathway. Genetic mutations that result in an over-expression of AGT are strongly associated with hypertension. We have previously shown that siRNA targeting maternal hepatic AGT in a transgenic model of preeclampsia (hAGT x hREN) resulted in lower blood pressure, a 90% reduction in AT1-AA activity, and normalized IUGR. The purpose of the present study is to examine the effect of silencing maternal hepatic AGT on maternal blood pressure and fetal growth in the reduced uterine placental perfusion pressure (RUPP) model of PE. Methods: Pregnant Sprague Dawley rats were divided into 4 groups: normal pregnant (NP, n=7); RUPP (n= 6); RUPP + siRNA (n =7); NP + siRNA (n=7). On day 12 of gestation (GD), siRNA was subcutaneously injected into rats (10mg/kg), GD14 the RUPP surgery was performed, GD18 carotid catheters inserted, and GD19 conscious blood pressure (MAP) and fetal weight was recorded. Results: MAP was elevated in RUPP vs. NP (134±6 vs. 101±4 mmHg, p< 0.05), but was lower in RUPP + siRNA (117±4 mmHg) and unchanged in the NP+siRNA (92±3 mmHg) group compared to NP. Average fetal weights by group were 2.30±0.09 g (NP), 1.89±0.10 g (RUPP), 2.38±0.09 g (NP+siRNA), and 2.12±0.06 (RUPP+siRNA). A one-way ANOVA indicates a significant reduction in pup weights between NP and RUPP, but not NP+siRNA and RUPP+siRNA, indicating administration of siRNA to RUPP rats prevented the decrease in fetal weight. Conclusion: Administration of AGT siRNA to RUPP rats blunts the increase in blood pressure and prevents a decrease in fetal weights in response to placental ischemia and thus could be a potential therapy for management of preeclampsia and other hypertensive disorders of pregnancy. Research Supported by Alnylam & T32HL105324,
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