Effects of 2-methoxyestradiol administration in mouse models purported to show signs of preeclampsia and fetal growth restriction

Plasma concentration of 2-methoxyestradiol (2-ME) and placental expression of catechol-O-methyltransferase(COMT) are elevated in normal pregnancy, but reduced in women with preeclampsia (PE). Women with PE and fetal growth restriction (FGR)exhibit decreased utero-placental blood flow. Catechol-O-methyltransferase knockout mice (COMT-/-) and female CBA/J mice mated with male DBA/2 mice (CBA/J × DBA/2)show many signs of PE during pregnancy and deliver growth-restricted pups. 2-ME is known to induce significant vasorelaxation of uterine arteries from pregnant mice. We hypothesized that 2-ME administration during pregnancy will lead to an increase in uterine artery blood flow velocity in COMT-/- and CBA/J × DBA/2 mice and therefore ameliorate PE-like signs and rescue fetal growth in these animal models. Pregnant COMT-/- and their controls (C57BL/6),and CBA/J × DBA/2 and their controls (CBA/J × BALB/c),were injected subcutaneously daily with 10 ng of 2-ME or vehicle (olive oil) from gestational day (GD) 12.5 to 17.5. There was no significant effect of genotype/strain or treatment on maternal blood pressure, uterine artery blood flow velocity or fetal growth. A perturbed phenotype only occurred in the COMT-/- mice in regard to umbilical artery flow velocity, proteinuria and 2-ME levels. Administration of 2-ME led to normalization ofumbilical artery blood flow velocity and proteinuria in COMT-/- mice. The utility of 2-ME in cases of PE and FGR needs to be further explored in PE models that exhibit more severe disease phenotypes.