Placental ischemia-induced increases in brain water content and cerebrovascular permeability: role of TNF-α

Cerebrovascular complications and increased risk of encephalopathies are characteristic of pre-eclampsia and contribute to 40% of preeclampsia/eclampsia-related deaths. Circulating tumor necrosis factor-alpha (TNF-alpha) is elevated in preeclamptic women, and infusion of TNF-alpha into pregnant rats mimics characteristics of preeclampsia. While this suggests that TNF-alpha has a mechanistic role to promote preeclampsia, the impact of TNF-alpha on the cerebral vasculature during pregnancy remains unclear. We tested the hypothesis that TNF-alpha contributes to cerebrovascular abnormalities during placental ischemia by first infusing TNF-alpha in pregnant rats (200 ng/day ip, from gestational day 14 to 19) at levels to mimic those reported in preeclamptic women. TNF-alpha increased mean arterial pressure (MAP, P < 0.05) and brain water content in the anterior cerebrum (P < 0.05); however, TNF-alpha infusion had no effect on blood-brain barrier (BBB) permeability in the anterior cerebrum or posterior cerebrum. We then assessed the role of endogenous TNF-alpha in mediating these abnormalities in a model of placental ischemia induced by reducing uterine perfusion pressure followed by treatment with the soluble TNF-alpha receptor (etanercept, 0.8 mg/kg sc) on gestational day 18. Etanercept reduced placental ischemia-mediated increases in MAP, anterior brain water content (P < 0.05), and BBB permeability (202 +/- 44% in placental ischemic rats to 101 +/- 28% of normal pregnant rats). Our results indicate that TNF-alpha mechanistically contributes to cerebral edema by increasing BBB permeability and is an underlying factor in the development of cerebrovascular abnormalities associated with preeclampsia complicated by placental ischemia.