293. Preclinical assessment of new generation antiplatelet therapies to prevent preeclampsia

Abstract

Key pathophysiological steps in preeclampsia include 1) placental oxidative stress, 2) elevated sFlt1 and 3) endothelial dysfunction. While the antiplatelet drug aspirin has shown potential to prevent preeclampsia, its effectiveness remains limited. New generation antiplatelet drugs (Clopidogrel, Prasugrel and Ticagrelor) have distinct properties beyond antiplatelet actions (inflammation and endothelial dysfunction), thus may be more effective to prevent preeclampsia. We examined whether new generation antiplatelet drugs are better than aspirin at countering various pathophysiological steps in models of preeclampsia. Methods Primary human cytotrophoblast, placental explants and endothelial cells (HUVEC and uterine microvascular (UtMVs)) were treated with increasing doses of Clopidogrel, Prasugrel, Ticagrelor or Aspirin (0–100 μM). Endothelial dysfunction was induced and antiplatelet agents were added. Functional assays measured the adherence of primary human monocytes to stimulated endothelial cells. Media and cell lysates were collected to assess 1) ROS production, 2) antioxidant response element signaling pathways, 3) production of vasoactive mediators, 4) production of sFlt1, PlGF and pro-inflammatory mediators and 4) markers of endothelial dysfunction. Results New generation antiplatelet agents induced nuclear Nrf2 translocation (antioxidant transcription factor), increased antioxidant gene expression (HO-1, NQO1 and GCLC). Consistently reactive oxygen species (ROS) production was reduced with new generation antiplatelet treatment. Furthermore the new generation antiplatelets potently reduced sFlt1 secretion from preeclamptic placental explants, and importantly they also increased PlGF mRNA expression. Antiplatelet agents rescued endothelial dysfunction, mitigating monocyte-endothelial adhesion, and reduced VCAM1 and ET-1 expression (both mRNA and protein) and enhanced eNOS activity. Aspirin however had no beneficial effects in our in vitro/ex vivo models of preeclampsia. Conclusions In contrast to aspirin, new generation antiplatelets potently upregulate antioxidant defences, reduce ROS formation, decrease sFlt1 secretion, enhance activity of vasoactive mediators and counter endothelial dysfunction in human models of preeclampsia. Given they are classified as category B/C drugs, they represent exciting candidate therapies to prevent preeclampsia.