Artificial oxygen carriers rescue placental hypoxia and improve fetal development in the rat pre-eclampsia model

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.

Overview of Potential Clinical Applications of Hemoglobin Vesicles (HbV) as Artificial Red Cells, Evidenced by Preclinical Studies of the Academic Research Consortium

“…In a condition where plasma flow is retained in spite of suppressed RBC supply, the presence of HbV in plasma can sustain the oxygen supply to peripheral tissues. This concept supports the efficacy of HbV as oxygen therapeutics for oxygenation of ischemic brain tissues [34], skin flap ischemic tissues [35,36], pre-eclampsia [37], etc. (Table 2).…”

Hypertension in pregnancy: Taking cues from pathophysiology for clinical practice

“…A pilot study of plasmapheresis in pregnant women effectively reduced BP and proteinuria . In a rat preeclampsia model, nano‐scale artificial oxygen carriers (hemoglobin vesicles) reduced levels of antiangiogenic proteins and improved fetal intrauterine growth . Blocking ETA receptors could also prove effective in PE.…”

“…36 39 In a rat preeclampsia model, nano-scale artificial oxygen carriers (hemoglobin vesicles) reduced levels of antiangiogenic proteins and improved fetal intrauterine growth. 40 Blocking ETA receptors could also prove effective in PE. However, ETA is important in fetal development during the first trimester; thus, such therapy needs to be administered later in pregnancy or in a compound that does not cross the placental barrier.…”

Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers

“…Our group is currently planning to draft a protocol for a clinical study (Phase I) according to the guidance for O 2 carrier products by The Society of Blood Substitutes Japan [114]. In addition to functioning as a RBC substitute, we and other colleagues recently showed another potential use for HbV based on its O 2 and carbon monoxide transport characteristics, which lead us to expect that it has a variety of other applications [115,116,117,118,119]. Thus, HbV has enormous potential for clinical applications, and the first clinical trials of HbV toward realization in clinics are being awaited.…”