Potential New Non-Invasive Therapy Using Artificial Oxygen Carriers for Pre-Eclampsia

Abstract

The molecular mechanisms of pre-eclampsia are being increasingly clarified in animals and humans. With the uncovering of these mechanisms, preventive therapy strategies using chronic infusion of adrenomedullin, vascular endothelial growth factor-121 (VEGF-121), losartan, and sildenafil have been proposed to block narrow spiral artery formation in the placenta by suppressing related possible factors for pre-eclampsia. However, although such preventive treatments have been partly successful, they have failed in ameliorating fetal growth restriction and carry the risk of possible side-effects of drugs on pregnant mothers. In this study, we attempted to develop a new symptomatic treatment for pre-eclampsia by directly rescuing placental ischemia with artificial oxygen carriers (hemoglobin vesicles: HbV) since previous data indicate that placental ischemia/hypoxia may alone be sufficient to lead to pre-eclampsia through up-regulation of sFlt-1, one of the main candidate molecules for the cause of pre-eclampsia. Using a rat model, the present study demonstrated that a simple treatment using hemoglobin vesicles for placental ischemia rescues placental and fetal hypoxia, leading to appropriate fetal growth. The present study is the first to demonstrate hemoglobin vesicles successfully decreasing maternal plasma levels of sFlt-1 and ameliorating fetal growth restriction in the pre-eclampsia rat model (p < 0.05, one-way ANOVA). In future, chronic infusion of hemoglobin vesicles could be a potential effective and noninvasive therapy for delaying or even alleviating the need for Caesarean sections in pre-eclampsia.

Placental vascular alterations are associated with early neurodevelopmental and pulmonary impairment in the rabbit fetal growth restriction model

“…Labyrinth volume reduction was driven by a reduction in fetal capillaries at histological level and coincided with the reduction in fetoplacental vessel volume on microcomputed tomography. Although this is the first published experience using this technique in the rabbit, labyrinth alterations have been previously described in several other FGR models, including those induced by maternal undernutrition 35,36 , exogenous 37,38 and endogenous 39 glucocorticoid excess, heavy metal exposure 40 , NO synthetase inhibition 41,42 , and systemic inflammation 43 . Furthermore, labyrinth underdevelopment, and particularly fetal vessel reduction, has www.nature.com/scientificreports/ been associated with reduced levels of different placental vascular endothelial growth factor (VEGF) mRNAs 38 , and glucose transport capacity 39,44 .…”

Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives

“…HbV, which is a type of Nano-HBOC with a nanoscale size and no blood group antigens, can pass through narrow placental spiral arteries and capillaries to provide an efficient O 2 supply to the placenta [ 247 , 248 ]. Ohta et al [ 249 ] intravenously injected HbV into a rat preeclampsia model. The results showed that HbV alleviated fetal hypoxia by supplying oxygen while improving fetal growth restriction in a murine model of preeclamptic pregnancy.…”

Current perspectives of artificial oxygen carriers as red blood cell substitutes: a review of old to cutting-edge technologies using in vitro and in vivo assessments

“…AOC products are feasible in traumatic conditions as well as in austere environments where blood donation is impossible. In addition, these may be used in medical treatments such as elective and cardiovascular surgeries (Spahn 2018 ; Haldar et al 2019 ); they are effective in alleviating ischemic conditions such as cerebral hypoxia (Kaneda et al 2014 ) and fetal ischemia (Ohta et al 2017 ). In addition, they are non-perishable, stable to supply, and economically feasible (Bialas et al 2019 ).…”