43 New generation antiplatelet therapies to prevent preeclampsia

Abstract

Introduction Preeclampsia is a serious complication of pregnancy. Responsible for thousands of maternal and fetal deaths worldwide, there is no cure. Key pathophysiological steps in preeclampsia include 1) placental damage and oxidative stress, 2) elevated sFlt1 and soluble endoglin (sEng) and 3) endothelial dysfunction. While the antiplatelet drug aspirin is used clinically to prevent preeclampsia, its effectiveness, if any, remains limited. New generation antiplatelet therapies (Clopidogrel, Prasugrel and Ticagrelor) have health benefits beyond anti-thrombus formation (they reduce oxidative damage, inflammation and endothelial dysfunction) and thus may be more effective to prevent preeclampsia. We examined whether new generation antiplatelet agents can counter the pathophysiological steps in human preeclampsia models and compared their efficacy directly to aspirin. Methods Primary human trophoblast, placental explants and endothelial cells (human umbilical vein endothelial cells (HUVECs) and uterine microvascular cells (UtMVs)) were treated with increasing doses of Aspirin, Clopidogrel, Prasugrel or Ticagrelor (0–100 μ M). Endothelial dysfunction was induced by addition of the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)- α (10 μ g/mL) stimulation of endothelial cells (antiplatelet agents were titrated in). Peripheral blood monocytes were isolated and applied to stimulated HUVECs; their adhesion was assessed flurometrically. Media and cell lysates were collected to assess 1) antioxidant response element signaling pathways, 2) anti-angiogenic factors (sFlt1/sEng) and the pro-angiogenic factor PlGF and 3) endothelial dysfunction (vascular cell adhesion molecule-1 (VCAM1) and endothelin-1 (ET-1)). Results New generation antiplatelet agents induced nuclear Nrf2 translocation (antioxidant transcription factor) and increased antioxidant gene expression: HO-1, NQO1 and GCLC. In contrast, aspirin did not affect antioxidant pathways. Furthermore Clopidogrel, Prasugrel and Ticagrelor potently reduced sFlt1 secretion from both placental and endothelial cells; and sEng secretion from endothelial cells. In contrast, aspirin did not affect sFlt or sEng secretion. PlGF mRNA expression was significantly enhanced with new generation anti-platelet treatment. Clopidogrel and Prasugrel rescued endothelial dysfunction, mitigating TNF α induced monocyte-endothelial adhesion, as well as VCAM1 and ET-1 mRNA and protein expression. Again aspirin had no effect. Conclusions New generation antiplatelet therapies potently upregulate anti-oxidant defences, decrease sFlt1/sEng secretion 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.