Radical change for the fetus

Abstract

Fetal cardiovascular and metabolic responses to hypoxaemia are central to intact fetal survival and are well conserved across species. For instance, although human labour is commonly associated with transient fetal hypoxaemia caused by uterine contractions, the prevalence of a common manifestation of fetal hypoxaemia, neonatal hypoxic–ischaemic encephalopathy (HIE), is low. It is only when fetal physiological compensations are overwhelmed or blunted that tissue damage occurs, leading to fetal death or long-term disability, such as cerebral palsy. One aspect of the acute cardiovascular defence, the redistribution of cardiac output to favour essential organs such as the adrenals, myocardium and brain, is also central to fetal survival if hypoxaemia is maintained, as observed with fetal growth restriction as a result of placental dysfunction. Any major advance in understanding the mechanisms underlying these responses is therefore to be welcomed. In this context, the work published by Herrera, Kane and colleagues (Herrera et al. 2012) in this issue of The Journal of Physiology, is the latest example of importance. This research group has discovered that in the fetal circulation, reactive oxygen species (ROS) interact with nitric oxide (NO) to modify vascular function, promoting a vascular ‘oxidant tone’ under basal and stimulated conditions. This oxidant tone or fraction can be manipulated in either direction, with consequent changes in vascular resistance and thereby blood flow. Hence, during basal conditions, administration of antioxidants, such as vitamin C or melatonin, into the fetal circulation quenches ROS and increases NO bioavailability. This leads to a decrease in umbilical vascular resistance and an increase in umbilical blood flow, demonstrating that the oxidant tone maintains umbilical perfusion under check even under basal conditions (Thakor et al. 2010a). During acute fetal hypoxia, hypoxia-induced ROS limits NO bioavailability in the fetal peripheral circulation. This effect contributes to the chemoreflex and endocrine constrictor mechanisms that redistribute the fetal cardiac output away from non-essential vascular beds towards the brain, i.e. the oxidant tone contributes to the fetal brain sparing effect during acute hypoxia (Thakor et al. 2010b). Most recently, Giussani's group has also shown that fetal treatment with statins, another strategy to increase NO bioavailability, also modifies the vascular oxidant tone with predictable consequences on the fetal peripheral vasoconstrictor response to acute hypoxia (Kane et al. 2012). Further, maternal treatment with antioxidants in rat pregnancy complicated by fetal chronic hypoxia was protective and increased birth weight (Richter et al. 2012). The current study in this issue of The Journal traces the origins of this pro-oxidant mechanism. Xanthine oxidase (XO) is known to be stimulated by hypoxia and may act as a source of ROS, limiting NO bioavailability. To assess its role in fetal cardiovascular control a high dose of allopurinol, a xanthine oxidase inhibitor, was given to pregnant ewes and the fetal response observed under basal and stimulated conditions. Maternal allopurinol caused an increase in umbilical arterial blood flow and conductance, providing proof of concept that XO-derived free radicals have a role on the regulation of fetal cardiovascular function under basal conditions. XO blockade also blunted the pressor response in the femoral circulation to phenylephrine, suggesting that XO-generated ROS may also have a role in the pressor and peripheral vasopressor responses to acute hypoxia. The data also have potential translational relevance. ROS are implicated in the aetiology of maternal pre-eclampsia and of fetal brain injury leading to a number of reported or ongoing trials where anti-oxidants have been given to the mother during pregnancy. In particular, allopurinol has been tested as a potential neuro-protectant in neonates with HIE and is now being assessed as an antenatal treatment (Kaandorp et al. 2010). The study by Herrera et al. shows that allopurinol in very high doses in sheep can have potentially beneficial as well as detrimental effects. The associated increase in umbilical blood flow will improve placental efficiency and increase fetal substrate delivery. However, blunting the fetal peripheral vascular response to pressor agents or acute hypoxia would be detrimental if it meant the fetus could not maintain perfusion to the cerebral circulation during a hypoxic challenge. However, there is a caveat in this line of thinking. While allopurinol-induced increases in NO bioavailability may depress constriction in fetal circulations that vasoconstrict during hypoxia (e.g. femoral), it may actually maintain or enhance blood flow in fetal circulations that vasodilate during acute hypoxia (e.g. cerebral). The maintenance of perfusion pressure is therefore critical. Studies that include parallel measurement of peripheral and cerebral blood flow in the sheep fetus during acute hypoxia in the presence of antioxidant treatment in doses that are administered to humans are required before the potential consequences of fetal anti-oxidant treatment are known.