Abstract
Heme Oxygenase-1 (HO-1) has been shown to play a pivotal role in pregnancy outcome and its ablation leads to abnormal placentation, intrauterine fetal growth restriction (IUGR) and subsequent intrauterine fetal death. Carbon monoxide (CO) has been found to mimic the protective effects of HO-1 activity, rescuing HO-1-deficient fetuses. This gasotransmitter arises in biological systems during the oxidative catabolism of heme by HO. Here, we explored the potential of CO in preventing IUGR and established the optimal doses and therapeutic time window in a clinically relevant mouse model. We additionally investigated the pathways activated upon CO application in vivo. We established 50 ppm as the best lowest dose of CO necessary to prevent growth restriction being the optimal time frame during days 3 to 8 of mouse pregnancy. CO lead to higher fetal and placental weights and avoided fetal death without showing any pathologic effects. CO breathing further suppressed inflammatory responses, diminished placenta apoptosis and complement deposition and regulated placental angiogenesis. Our results confirm the protective role of the HO-1/CO axis and point this gas as an emerging therapeutic possibility which is worth to further explore.
Highlights
In mammals, most embryonic losses occur during early pregnancy [1,], which represents a critical period of gestation because of the major developmental events that take place, including placentation and embryonic organogenesis [3,4,]
50 ppm Carbon monoxide (CO) application during days 3-8 of pregnancy was effective in preventing fetal loss while not provoking deleterious effects in mothers or pups The model chosen to explore the effect of CO application is a relevant one for studying intrauterine growth restriction (IUGR) [17]
It has been shown that in this particular model, the heme oxygenase-1 (HO-1) expression is diminished in placenta from mice of the IUGR combination compared to the controls [20,21]
Summary
Most embryonic losses occur during early pregnancy [1,], which represents a critical period of gestation because of the major developmental events that take place, including placentation and embryonic organogenesis [3,4,]. Reduced placental vascular development and increased vascular resistance are associated with early embryonic mortality [8,]. Exogenous supply of CO at low concentrations can regulate many physiological processes without apparent toxicity and is able to restore the immunoregulatory and cytoprotective effects of HO-1 after its pharmacologically inhibition in a variety of pathologies [13,14,15]. This gasotransmitter is an endogenous product of heme degradation through HO-1. CO has been implicated in the angiogenic response associated with induction of HO-1 [14,15]
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