The effects of cerebral ischemia on white matter changes in ovine fetuses were examined after exposure to bilateral carotid artery occlusion. Fetal sheep were exposed to 30 min of ischemia followed by 48 (I/R-48, n ϭ 8) or 72 (I/R-72, n ϭ 10) h of reperfusion or control sham treatment (control, n ϭ 4). Serial coronal sections stained with Luxol fast blue/hematoxylin and eosin were scored for white matter, cerebral cortical, and hippocampal lesions. All areas received graded pathologic scores of 0 to 5, reflecting the degree of injury where 0 ϭ 0%, 1 ϭ 1% to 25%, 2 ϭ 26% to 50%, 3 ϭ 51% to 75%, 4 ϭ 76% to 95%, and 5 ϭ 96% to 100% of the area damaged. Dual-label immunofluorescence using antibodies against glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) were used to characterize white matter lesions. Basic fibroblast growth factor (FGF-2) was measured in the frontal cortex by ELISA. Results of the pathologic scores showed that the white matter of the I/R-72 (2.74 Ϯ 0.53, mean Ϯ SEM) was more (p Ͻ 0.05) damaged when compared with the control (0.80 Ϯ 0.33) group. Cortical lesions were greater (p Ͻ 0.05) in the I/R-48 (2.12 Ϯ 0.35) than the control (0.93 Ϯ 0.09) group. White matter lesions were characterized by reactive GFAP-positive astrocytes and a loss of MBP in oligodendrocytes. The ratio of MBP to GFAP decreased (p Ͻ 0.05) as a function of ischemia, indicative of a proportionally greater loss of MBP than GFAP. FGF-2 concentrations were higher (p Ͻ 0.05) in the I/R-72 than the control group and there was a direct correlation between the pathologic scores (PS) and FGF-2 concentrations (FGF-2 ϭ e (1.6 PS-0.90) ϩ 743, n ϭ 17, r ϭ 0.73, p Ͻ 0.001). We conclude that carotid artery occlusion results in quantifiable white matter lesions that are associated with a loss of MBP from myelin, and that FGF-2, a purported mediator of recovery from brain injury in adult subjects, increases in concentration in proportion to the severity of brain damage in the fetus. Hypoxic/ischemic brain injury is the single most important neurologic problem occurring in the perinatal period. There is substantial evidence to suggest that a major component of brain injury is related to ischemia alone or hypoxia/ischemia (1-3). Although many studies have characterized the neuronal outcome to a variety of ischemic insults, white matter injury has not been well studied (4).Nonetheless, white matter injury has been described recently in neonatal (5-7) and adult rats (8) using various forms of carotid artery occlusion. Several studies have found white matter injury in fetal sheep that were subjected to hypoxemia (9), systemic hypotension (10), bilateral carotid artery occlusion (11, 12), and repeated umbilical cord occlusion (13-16). However, these studies have not quantified the white matter lesions or defined the pattern of white matter injury in multiple brain regions. Although neuronal injury arising from bilateral carotid artery occlusion in the ovine fetus has been extensively described (17)(18)(19), the accompanying white ...