Exploring the potential of low doses carbon monoxide as therapy in pregnancy complications

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,]. Placentation comprises extensive angiogenesis in maternal and placental tissues, accompanied by a marked increase in uterine and umbilical blood flows [6,7]. Reduced placental vascular development and increased vascular resistance are associated with early embryonic mortality [8,]. Factors influencing placental vascular development and function have a dramatic impact on fetal growth and development, and thereby on neonatal survival and growth [10,11]. We have recently identified the enzyme heme oxygenase-1 (HO-1) as a pivotal factor in supporting placentation [12]. The protective effects of HO-1 on placentation can be mimicked by administering mice partially deficient in HO-1 (Hmox1+/-) with carbon monoxide (CO, 12). Exogenous supply of CO at low concentrations can regulate many physiological processes without apparent toxicity and is able indeed to restore the immunoregulatory and cytoprotective effects of HO-1 after its pharmacologically inhibition in a variety of pathologies [13-15]. This gasotransmitter is an endogenous product of heme degradation through HO-1. CO has been shown to exert cytoprotective effects by reducing pro-inflammatory mediators, preventing vascular constriction, decreasing platelet aggregation and inhibiting apoptosis [13] and was proposed to be a placenta vasodilator [16]. CO has been also implicated in the angiogenic response associated with induction of HO-1 [14,15].Having learned that HO-1 is crucial for placentation and intrauterine fetal survival via CO, we aim here to investigate the therapeutic potential of CO in avoiding pregnancy complications. To do so we established the optimal doses and time frame of treatment with CO via inhalation in a clinically relevant model of intrauterine growth restriction