An investigation into the effect of in utero hypoxia on cerebral blood vessels and brain activity in late gestation fetal sheep.

Fetal hypoxia contributes significantly to the pathogenesis of permanent perinatal brain injury. Cerebrovascular pathology following hypoxia can lead to devastating and debilitating brain injury, such as that seen following stroke and haemorrhage, but the effect of in utero fetal hypoxia on the developing cerebrovasculature is not well understood. In the adult brain, robust up-regulation of vascular endothelial growth factor (VEGF) occurs following hypoxia and cerebral ischemia which results in the formation of new blood vessels, as an adaptive response to protect and repair the brain from hypoxic injury. However, newly-formed blood vessels are fragile and prone to rupture. The aims of the studies described in this thesis were to determine how a single brief, but severe episode of fetal hypoxia in late gestation in sheep affects VEGF expression and the cerebral vasculature. We also determined the effects of this global hypoxia on fetal and neonatal behaviour to determine if the fetal brain can repair itself following a single brief hypoxic insult. The results show that 48 h after an in utero hypoxic insult, produced by 10 min of complete umbilical cord occlusion, the distribution of mean blood vessel size is greater in white matter but not gray matter, and there was greater blood vessel-associated VEGF expression white matter compared to gray matter. This was associated with disruption in blood brain barrier (BBB) permeability seen by increased extravasation of plasma albumin in white matter. When the fetuses were left in utero (5 – 10 days following UCO) until the onset of labour, increased VEGFR-2 expression was again seen in white, not gray matter. These studies highlight the importance of assessing VEGF/VEGFR system following in utero hypoxia in the developing fetal brain. Studies assessing both fetal and newborn behaviour following in utero global hypoxia showed that fetal electrocortical (ECoG) activity and breathing movements were disturbed throughout late gestation, and after birth there were delays in the newborn lamb achieving important behavioural milestones such as the ability to stand, use all four legs, and find the udder and suckle. Therefore, it is concluded that an antepartum hypoxic event late in gestation does not result in the fetal brain being able to recover fully, resulting in persistent and profound changes in brain structure and pre- and post-natal behaviour