Preeclampsia is a serious pregnancy complication, but treatment strategies are extremely limited. Systemic vasoconstriction is a key feature of preeclampsia. Previously, we identified that the new generation antiplatelet agent prasugrel could prevent vasoconstriction of human maternal systemic arteries. In this study, we aimed to examine the mechanisms of prasugrel action, in particular whether prasugrel works through the nitric oxide pathway (important in regulation of vascular tone).
Pregnant CBA X C57BL/6 (F1) mice received 50mg/kg/day L-NAME (nitric oxide synthase inhibitor; modelling preeclampsia), and 10mg/kg prasugrel or control (vehicle; DMSO) injections from D7.5-D17.5 gestation (n=10/group). Maternal blood pressure was measured at D14.5 and D17.5. Maternal blood was collected (D17.5) to assess circulating sFLT-1, CRP, and ET-1. Fetal and placental size and morphology were assessed (D17.5). Human omental fat biopsies were collected from pregnant individuals at term Caesarean section (n=3). Omental arteries were dissected, pre-constricted with ET-1 and then treated with 0.2-100µM prasugrel or vehicle to assess vasodilation (wire myography). Endothelium-independent effects were examined by pre-incubating arteries with 300uM L-NAME or removing the endothelium.
Prasugrel significantly reduced maternal blood pressure at D14.5 and D17.5, and reduced circulating sFLT-1 and CRP, but not ET-1. Fetuses of prasugrel-treated dams had increased crown-to-rump length, with no change in fetal weight or litter size. Prasugrel administration did not alter placental weight, but significantly expanded the placental blood space. Preliminary vascular assessment demonstrated prasugrel induced vasodilation of human omental arteries pre-constricted with ET-1. Pre-incubation with L-NAME and denuding the endothelium had no effect on prasugrel-induced vasodilation.
This study demonstrates that prasugrel mitigates multiple aspects of the pathogenesis that underpins preeclampsia, irrespective of nitric oxide levels or endothelial function. Together, these data further support the novel use of prasugrel in treatment of preeclampsia, an urgent unmet need in obstetric medicine.