Preeclampsia is a complication of pregnancy with significant morbidity and mortality for the mother and the fetus. Presumptions are made that placental hypoxia has a causative role in the clinical syndrome. Furthermore, soluble fms-like tyrosine kinase 1 (sFLT-1) has been shown to have a role in the maternal syndrome of preeclampsia. We investigated the relationship between uteroplacental ischemia (UPI), the maternal clinical syndrome of preeclampsia and sFLT-1 in non-human primates. The induction of UPI in a pregnant non-human primate resulted in the development of a clinical entity analogous to human preeclampsia. This was illustrated by the increase in blood pressure, development of proteinuria, and renal histological changes identical to human preeclampsia. A significant elevation in the placental and peripheral blood mononuclear cell sFLT-1 mRNA expression was noted, translating to a significant elevation in circulating sFLT-1. Thus, this sequence suggests that a pathogenic reduction in placental perfusion results in the development of the maternal syndrome of preeclampsia and an increase in circulating sFLT-1, which is derived both from placental and extra-placental sources.

Hypertensive disorders of pregnancy are associated with vascular dysfunction in the pregnancy and an increased risk of long-term cardiovascular disease (CVD) in the mother. What remains to be understood is whether the length, severity of the disease, the treatment of hypertension in pregnancy, or the subtype of hypertensive disorders of pregnancy are significant predictors of future CVD. We undertook a retrospective cohort study to review all women who gave birth at a tertiary hospital in Sydney between the years 1980 and 1989 (n=31 656). A cohort of women was further defined by having hypertension during the antenatal, intrapartum, or postnatal periods (n=4387). Randomly selected records of women (n=1158) with a hypertensive disorder of pregnancy were individually reviewed to collect data on their pregnancy and pregnancy outcomes. The entire cohort then underwent linkage analysis to future CVDs. Women who presented with gestational hypertension were at greater risk of future hypertension and ischemic heart disease compared with the women who were diagnosed with preeclampsia. There was no significant difference between the women who were treated with antihypertensive medication and the women who did not receive antihypertensive medication or the duration of hypertensive disorders of pregnancy and future admission for CVD, although severity of hypertension tracked with increased risk of future hypertension in all groups. This study demonstrated that all women who present with any of the subtypes of hypertensive disorders in pregnancy are at significant risk of future CVD compared with women who remain normotensive during their pregnancy.

Preeclampsia (PE) is a placentally-induced hypertensive disorder of pregnancy that is associated with significant morbidity and mortality to mothers and fetuses. Clinical manifestations of preterm PE result from excess circulating soluble vascular endothelial growth factor receptor FLT1 (sFLT1 or sVEGFR1) of placental origin. Here we identify short interfering RNAs (siRNAs) that selectively silence the three sFLT1 mRNA isoforms primarily responsible for placental overexpression of sFLT1. Full chemical stabilization in the context of hydrophobic modifications enables productive siRNA accumulation in the placenta (up to 7% of injected dose) and reduces circulating sFLT1 in pregnant mice (up to 50%). In a baboon PE model, single dose of siRNAs suppressed sFLT1 overexpression and clinical signs of PE. Our results demonstrate RNAi-based extra-hepatic modulation of gene expression with non-formulated siRNAs in non-human primates and establish a path toward a new treatment paradigm for patients with preterm PE.