VEGF expression and microvascular responses to severe transient hypoxia in the fetal sheep brain

Abstract

Fetal hypoxia contributes significantly to the pathogenesis of permanent perinatal brain injury. We hypothesized that hypoxia-induced cerebral angiogenesis and microvascular changes would occur in fetal sheep subjected to a severe hypoxic insult produced by umbilical cord occlusion (UCO) for 10 min. At 124-126 d of gestation, singleton fetal sheep underwent surgery for implantation of catheters and placement of an inflatable cuff around the umbilical cord. A 10-min UCO or sham UCO (n = 5) was induced at 130 d gestation. The fetal brain was collected at 24 h (n = 5) or 48 h (n = 4) after UCO for immunohistochemical analysis of vascular endothelial growth factor (VEGF), Ki67, and serum albumin. By 48 h after UCO, the percentage of blood vessels expressing VEGF had increased in the subventricular zone, periventricular and subcortical white matter, corpus callosum, and cortex. Alterations in vascular permeability (albumin extravasation) were observed only in the periventricular and subcortical white matter and the subventricular zone following UCO. The upregulation of VEGF expression and increased leakage of plasma protein in the fetal sheep brain show that the microvasculature in white matter is sensitive to hypoxia in the near-term brain.