Oxidative stress contributes to soluble fms-like tyrosine kinase-1 induced vascular dysfunction in pregnant rats.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These data indicate elevated maternal sFlt-1 and decreased VEGF concentrations results in increased oxidative stress that contributes to vascular dysfunction during pregnancy.
Bridges
Jason P
JP
Department of Physiology and the Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Gilbert
Jeffrey S
JS
Colson
Drew
D
Gilbert
Sara A
SA
Dukes
Matthew P
MP
Ryan
Michael J
MJ
Granger
Joey P
JP
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000502:physiology; D051381:Rats; D013481:Superoxides / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
D013481:Superoxides; D009599:Nitroprusside; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1