title: Control of soluble fms-like tyrosine-1 (sFlt-1) production response to placental ischemia/hypoxia: role of tumor necrosis factor-α.
abstract: Although abnormal soluble fms-like tyrosine kinase-1 (sFlt-1) production is thought to be an important factor in the pathogenesis of preeclampsia (PE), the mechanisms that regulate the production of sFlt-1 during PE are unclear. While our laboratory has shown tumor necrosis factor-α (TNF-α) and sFlt-1 to be elevated in pregnant rats in response to placental ischemia, the importance of TNF-α in the regulation of sFlt-1 production is unknown. Therefore, the purpose of this study was to determine the role of TNF-α in mediating the increase in sFlt-1 in response to placental ischemia or hypoxia. Reductions in uterine perfusion pressure in pregnant rats significantly increased plasma levels of sFlt-1 and tended to increase TNF-α, an effect markedly attenuated by pretreatment with a TNF-α inhibitor etanercept (0.4 mg/kg). To further assess chronic interactions between TNF-α and sFlt-1, we examined a chronic effect of TNF-α infusion (50 ng/day) into normal pregnant rats to increase plasma sFlt-1 levels, as well as the effects of acute hypoxia on placental sFlt-1 production in the absence and presence of TNF-α blockade. Placental explants exposed to hypoxic conditions had enhanced TNF-α levels versus normoxic conditions, as well as increased sFlt-1 production. Pretreatment of placental explants with etanercept (15 μM) significantly reduced TNF-α levels in response to hypoxia but did not attenuate sFlt-1 production. These data suggest that while TNF-α may not play an important role in stimulating sFlt-1 production in response to acute hypoxia, a more chronic hypoxia, or placental ischemia may be an important stimulus for enhanced sFlt-l production.
authors.affiliation: Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, Jackson, MS 39216-4505, USA.
authors.forename: Sydney R
authors.initials: SR
authors.lastname: Murphy
authors.forename: B Babbette D
authors.initials: BB
authors.lastname: LaMarca
authors.forename: Marc
authors.initials: M
authors.lastname: Parrish
authors.forename: Kathy
authors.initials: K
authors.lastname: Cockrell
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D000068800:Etanercept; D005260:Female; D000860:Hypoxia / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000494:pharmacology; D007263:Infusions, Parenteral; D007511:Ischemia / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000097:blood / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1; D000068800:Etanercept