Oxidative Stress Contributes to Soluble Fms-Like Tyrosine Kinase-1 Induced Vascular Dysfunction in Pregnant Rats

Abstract

Recent evidence indicates that both increased oxidative stress and an altered balance between pro- and anti-angiogenic factors such as vascular-endothelial growth factor (VEGF) and the soluble VEGF receptor (sFlt-1) contribute to endothelial dysfunction in preeclampsia. We hypothesized that chronic infusion of sFlt-1 to mimic the increase observed in preeclamptic patients would reduce plasma VEGF concentrations, increase blood pressure (BP) and vascular superoxide levels, and cause endothelial dysfunction in the pregnant rat. Recombinant sFlt-1 was infused (500 ng/h) during days 13–18 of pregnancy. BP, fetal and placental weight, oxidative stress and vessel vasorelaxation were determined on day 18 of pregnancy. Plasma sFlt-1 concentrations (299 ± 33 vs. 100 ± 16 pg/ml; P < 0.01) and BP (117 ± 6 vs. 98 ± 4 mm Hg; P < 0.01) were increased, while plasma-free VEGF concentrations (570 ± 77 vs. 780 ± 48 pg/ml; P < 0.01) were decreased when compared to vehicle infused dams. sFlt-1 rats had smaller fetuses (1.3 ± 0.03 vs. 1.5 ± 0.04 g, P < 0.01) and placentas (0.41 ± 0.01 vs. 0.47 ± 0.02 g; P < 0.05). Placental (180 ± 66 vs. 24 ± 2.3 RLU/min/mg; P < 0.05) and vascular (34 ± 8 vs. 12 ± 5 RLU/min/mg; P < 0.05) superoxide production was increased in the sFlt-1 compared to vehicle infused rats. Vasorelaxation to acetylecholine (ACh) and sodium nitroprusside (SNP) were both decreased (P < 0.05) in the sFlt-1 infusion group compared to the vehicle and this decrease was attenuated (P < 0.05) by the superoxide scavenger Tiron. These data indicate elevated maternal sFlt-1 and decreased VEGF concentrations results in increased oxidative stress that contributes to vascular dysfunction during pregnancy.