Many animals experience hypoxia – low oxygen levels – in their environment on a regular basis. Fish living in shallow coastal rockpools experience hypoxia on a daily basis, and humans can also feel the effects of hypoxia when hiking at altitude in thin air. Developing embryos also experience bouts of hypoxia, some due to the mother's uterus contracting,which can reduce blood oxygen by 25%. During hypoxia, norepinephrine(noradrenaline) is released into the bloodstream to protect us from the negative effects of hypoxia by increasing the heart rate and either relaxing or constricting blood vessels to ensure blood supply to crucial organs. Because hypoxia provokes norepinephrine release, and developing embryos experience hypoxia, Margie Ream and her colleagues from Duke and Tufts Universities wondered whether norepinephrine protects developing fetal mice from the damaging effects of hypoxia.
Ream and her colleagues exposed pregnant mice to either normal oxygen levels or hypoxia and identified the embryos within the litter that had genetic mutations preventing norepinephrine synthesis. Then the team monitored the fetus's physiological responses to the oxygen conditions.
Compared with their normal siblings, the norepinephrine-deficient fetuses did not tolerate hypoxia well, and if they survived suffered from low heart rate, blood-flow problems, excessive bleeding, and even heart failure. Ream's team also concluded that, even under normal oxygen conditions, the cardiovascular systems of the norepinephrine-deficient fetal mice performed as if they were normal mice experiencing hypoxia. The team could only ensure the norepinephrine-deficient embryo's survival beyond 15 days if they supplied the mother with extraordinarily high oxygen levels, over twice the amount of oxygen found in normal air.
So, why not prevent hypoxia all together if the damaging effects are so profound? Evidently, exposure to hypoxia is crucial for some developmental processes; hypoxia is the only way to activate a special protein called HIF. When HIF is activated, it attaches to DNA and allows 155 genes to be decoded. If HIF is not activated in a developing fetus, certain genes are not turned on, and the animal may suffer eye damage, abnormal heart and liver development, and even shortened arms and legs. Therefore, it may be important for an animal to experience brief episodes of hypoxia to ensure HIF is activated so it can activate important genes and ensure proper development. Of course, excessive hypoxia is definitely problematic, and if not immediately fatal, can result in growth restrictions, pre-term delivery and even sudden infant death syndrome, as well as heart problems that can persist into adulthood. Ream and her colleagues concluded that an animal protects itself from the damaging effects of hypoxia by releasing norepinephrine, which helps maintain heart rate, blood flow and oxygen levels throughout the body. Meanwhile, developing fetuses that experience hypoxia are able to activate essential developmental pathways and develop properly because HIF is activated. However, if a fetus cannot synthesize norepinephrine, then the effects of hypoxia are magnified and death is almost certain.
Hypoxia clearly plays a key role in many cardiac developmental diseases. This study is the first to document the genes that are turned on in response to norepinephrine availability and hypoxia, and the findings provide a springboard for further understanding the essential role of the stress response to hypoxia and fetal development. Stress... some of us can't seem to live with it, but our lives apparently can't begin without it.
