title: Placental ischemia-induced increases in brain water content and cerebrovascular permeability: role of TNF-α.
abstract: Cerebrovascular complications and increased risk of encephalopathies are characteristic of preeclampsia and contribute to 40% of preeclampsia/eclampsia-related deaths. Circulating tumor necrosis factor-α (TNF-α) is elevated in preeclamptic women, and infusion of TNF-α into pregnant rats mimics characteristics of preeclampsia. While this suggests that TNF-α has a mechanistic role to promote preeclampsia, the impact of TNF-α on the cerebral vasculature during pregnancy remains unclear. We tested the hypothesis that TNF-α contributes to cerebrovascular abnormalities during placental ischemia by first infusing TNF-α in pregnant rats (200 ng/day ip, from gestational day 14 to 19) at levels to mimic those reported in preeclamptic women. TNF-α increased mean arterial pressure (MAP, P < 0.05) and brain water content in the anterior cerebrum (P < 0.05); however, TNF-α 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-α in mediating these abnormalities in a model of placental ischemia induced by reducing uterine perfusion pressure followed by treatment with the soluble TNF-α 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-α 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.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Junie P
authors.initials: JP
authors.lastname: Warrington
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Drummond
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi mjryan@umc.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001834:Body Water / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D002199:Capillary Permeability / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D000068800:Etanercept / Q000008:administration & dosage; D005260:Female; D005865:Gestational Age; D007511:Ischemia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010920:Placenta / Q000098:blood supply*; D011225:Pre-Eclampsia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D011247:Pregnancy; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
keywords: BBB permeability; cerebrovascular abnormalities; edema; preeclampsia; pregnancy