Control of soluble fms-like tyrosine-1 (sFlt-1) production response to placental ischemia/hypoxia: role of tumor necrosis factor-alpha

Murphy SR, LaMarca BB, Parrish M, Cockrell K, Granger JP. Control of soluble fms-like tyrosine-1 (sFlt-1) production response to placental ischemia/hypoxia: role of tumor necrosis factor-alpha. Am J Physiol Regul Integr Comp Physiol 304: R130-R135, 2013. First published November 28, 2012; doi:10.1152/ajpregu.00069.2012.-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-alpha (TNF-alpha) and sFlt-1 to be elevated in pregnant rats in response to placental ischemia, the importance of TNF-alpha in the regulation of sFlt-1 production is unknown. Therefore, the purpose of this study was to determine the role of TNF-alpha 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-alpha, an effect markedly attenuated by pretreatment with a TNF-alpha inhibitor etanercept (0.4 mg/kg). To further assess chronic interactions between TNF-alpha and sFlt-1, we examined a chronic effect of TNF-alpha 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-alpha blockade. Placental explants exposed to hypoxic conditions had enhanced TNF-alpha levels versus normoxic conditions, as well as increased sFlt-1 production. Pretreatment of placental explants with etanercept (15 mu M) significantly reduced TNF-alpha levels in response to hypoxia but did not attenuate sFlt-1 production. These data suggest that while TNF-alpha 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-1 production.