Abstract
Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.
Highlights
Considered to induce insufficient trophoblast invasion into the decidua portion of the placenta, resulting in incomplete, narrow placental spiral artery remodeling, leading to hypoxic conditions in the placenta
In the rat pre-eclampsia model, chronological changes in systolic blood pressure (SBP) levels were measured (Fig. 1a). 50 mg/day of L-NAME was intravenously infused through a catheter in the jugular vein for 7 consecutive days between gestational day 14 (G14) and G21
No statistical difference in SBP between the L-NAME-only treated and L-NAME + hemoglobin vesicle (HbV) treated groups was observed between G18 and G21
Summary
Considered to induce insufficient trophoblast invasion into the decidua portion of the placenta, resulting in incomplete, narrow placental spiral artery remodeling, leading to hypoxic conditions in the placenta. The same strategy can be applied to the placental spiral arteries in pre-eclampsia, in which artificial oxygen carriers treat fetal hypoxia by effectively supplying oxygen, passing through pathogenic narrow spiral arteries in the placenta induced or already established by pre-eclampsia To test this hypothesis, we used a rat pre-eclampsia model, in which continuous administration of the NO synthetase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) has been confirmed to induce narrow spiral artery formation, leading to maternal hypertension, placental apoptosis, increased serum tumor necrosis factor (TNF)-α , and fetal hypoxia - all of which have been implicated as being pathophysiological features of pre-eclampsia[6,7]. We applied to the pre-eclampsia model rat a daily HbV dose of 200 mg/kg/day, which has been proven to be the most effective and safe dosage to rescue hypoxic tissues in animal models in previous studies[4,5,8]
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