The role of TNF alpha in placental ischemia‐induced cerebrovascular abnormalities (1084.6)

While cerebrovascular events contribute to 40% of preeclampsia/eclampsia‐related deaths, the underlying contributing factors are unclear. Circulating tumor necrosis factor α (TNFα) is elevated in women with preeclampsia. We tested the hypothesis that TNFα contributes to cerebrovascular abnormalities that can be prevented by TNFα blockade. TNFα infusion in pregnant rats (100 ng/day ip, from gestational day 14 to 19) increased mean arterial pressure (MAP; 109 ± 3 vs. 99 ± 1 mmHg, p<0.05). Brain water content increased from 78.6 ± 0.1 to 79.0 ± 0.1% in TNFα‐infused rats (p<0.05), mainly due to increases in the anterior brain (79.6 ± 0.3 vs. 78.9 ± 0.1%; p<0.05). TNFα infusion increased hippocampal blood‐brain barrier (BBB) permeability, assayed using Evans blue extravasation, by 89.8 ± 27.2% (p<0.05). To assess the role of endogenous TNFα, a rat placental ischemia model of preeclampsia, induced by reducing uterine perfusion pressure, was treated with the soluble TNFα receptor, etanercept (0.8 mg/kg, sc.) on gestational day 18. Etanercept reduced placental ischemia‐mediated increases in 1) MAP (121 ± 3 to 115 ± 2 mmHg, vs.102 ± 2 in normal pregnant group; p<0.05), 2) anterior brain water content (80.1 ± 0.4 to 79.0 ± 0.2%, vs. 79.2 ± 0.2% in normal pregnant group; p<0.05), and 3) BBB permeability (202 ± 44 to 101 ± 28% of normal pregnant rats). Our results indicate that TNFα may mediate cerebral edema by increasing BBB permeability in response to placental ischemia. Thus, TNFα may be a target for preventing cerebrovascular complications associated with preeclampsia. Grant Funding Source : Supported by: NIH R01 HL108618, PPG HL51971 and AHA 13POST16240000