Hypoxia and Reactive Oxygen Species in Fetal Cardiovascular Function

Most people know that oxygen is indispensable for life, but few see it as a killer. Whether oxygen promotes life or threatens disease is dependent on its electrons. Safe oxygen has paired electrons. However, during under- or over-oxygenation, electrons may become unpaired, creating unstable molecules known as reactive oxygen species (ROS). Excessive generation of ROS, or oxidative stress, damages blood vessels leading to conditions such as heart disease, hypertension and pre-eclampsia. However, whether ROS and oxidative stress affects the blood vessels of the unborn child or unborn animal is unknown either in health or disease. This is of paramount importance because the unborn child and unborn animal is particularly susceptible to changes in oxygenation and, hence, the generation of ROS. Here, we propose that a number of effects of hypoxia on the cardiovascular system of the unborn child and unborn animal are secondary to the generation of ROS and oxidative stress. Adverse consequences of sustained under-oxygenation or chronic hypoxia in the unborn are intense constriction of blood vessels in its limbs, which promotes growth retardation and a strain on the developing heart. We will investigate whether increasing antioxidants in the fetus, with substances such as vitamin C, will reduce the effects of hypoxia on its blood vessels, protecting against the development of cardiovascular malfunction, even prior to birth.

Hypoxia/ischaemia reperfusion generates reactive oxygen species (ROS) and oxidative stress. In the endothelium, ROS bind to nitric oxide (NO), decreasing its bioavailability and, thereby, promoting vasoconstriction. Excessive ROS generation has established adverse consequences on vascular function. The international research effort investigating hypoxia-induced oxidative stress and vascular dysfunction has concentrated in the lung circulation, with regards to pulmonary hypertension and in the placenta, in association with miscarriage and pre-eclampsia. However, nothing is known about the effects of ROS and oxidative stress in the fetal vasculature either in health or disease. This is important as the unborn child and unborn animal are particularly susceptible to changes in oxygenation, and hence, ROS generation and oxidative stress. The key goal of this work is to test the hypothesis that the effects of hypoxia in the unborn's cardiovascular system are mediated, in part, via the generation of ROS and oxidative stress. Hypoxia in the fetus promotes peripheral vasoconstriction, intrauterine growth retardation and an increased load on the heart and major vessels. We will assess whether fetal exposure to antioxidants reduces the hypoxia-induced endothelial dysfunction, peripheral vasoconstriction, fetal growth restriction and the alterations in the development of the fetal heart and vasculature by increasing the bioavailability of NO. If true, antioxidant treatment may offer viable therapy against the adverse consequences of hypoxia in the unborn child and animal, offering not only novel biological information but possible clinical and veterinary intervention against the unwanted side effects of prenatal hypoxia - one of the most common challenges in fetal life in humans and animals.