Virtual Presentation SRB Virtual Awards 2020

Prasugrel reduces hypertension and vascular constriction in human and animal models of preeclampsia (#3)

Natasha de Alwis 1 , Yeukai TM Mangwiro 1 , Natalie K Binder 1 , Sally Beard 1 , Stephen Tong 1 , Tu'uhevaha Kaitu'u-Lino 1 , Natalie Hannan 1
  1. Department of Obstetrics and Gynaecology, University of Melbourne, Carlton, VIC, Australia

OBJECTIVE: Preeclampsia (PE) is a severe complication of pregnancy affecting 5-8% of pregnancies worldwide, but treatment strategies are seriously limited. Prasugrel is an anti-clotting drug used to treat acute coronary syndromes. We identified novel roles for prasugrel in mitigating key pathogenic aspects of preeclampsia, particularly enhancing vascular protection, reducing anti-angiogenic sFlt-1, vasoconstrictor endothelin-1 (ET-1), and endothelial dysfunction. This study aimed to determine whether prasugrel reduces a) maternal hypertension and b) vasoconstriction in models of disease.

METHODS: Pregnant CBA/C57BL6 (F1) mice were injected with 50mg/kg/day L-NAME and 10mg/kg prasugrel or control (vehicle) from D7.5 to D17.5 gestation (n=10/group). Blood pressure (BP) was measured at D14.5 and D17.5 gestation and blood collected to assess circulating sFlt-1 and ET-1 levels. Mesenteric arteries were dissected from pregnant mice at term (D17.5; n=6). Human omental arteries were collected from pregnant women at term (at Caesarean Section; n=4). Vasoreactivity was assessed via Wire Myography (DMT 620M). Vessels were pre-treated for 30 minutes with 100µM prasugrel or vehicle, followed by constriction with increasing doses of ET-1 (10-11M – 10-7M).

RESULTS: Mice treated with L-NAME demonstrated high BP, and elevated circulating levels of sFlt-1 and ET-1 (as observed in women with PE). Administration with prasugrel significantly reduced maternal BP at both D14.5 and D17.5 gestation. Furthermore, prasugrel treatment caused a reduction in elevated circulating sFlt-1, but not ET-1 levels. Mesenteric and omental arteries pre-treated with prasugrel demonstrated significantly reduced vasoconstriction to the potent vasoconstrictor ET-1 compared to arteries pre-incubated in control solution.

CONCLUSIONS: Prasugrel mitigated hypertension in a mouse model of disease, likely through reduction in anti-angiogenic sFlt-1, and reduced vascular constriction in mouse and human models. These data provide critical support for the novel use of prasugrel in prevention of PE that if translated, may offer considerable new hope for women and their babies.