Preeclampsia and
fetal growth restriction are responsible for the majority of maternal and perinatal morbidity and mortality associated with complicated pregnancies. Although their etiologies are complex and multifactorial, both are associated with increased uterine artery resistance.
Sildenafil citrate is able to rescue the dysfunction observed ex vivo in uterine arteries of women with
preeclampsia. The ability of
sildenafil citrate to increase uterine artery vasodilation, thereby decreasing uterine artery resistance and, hence, ameliorated
preeclampsia and
fetal growth restriction, was tested in a mouse model of
preeclampsia, the
catechol-O-methyl
transferase knockout mouse (COMT(-/-)). COMT(-/-) and C57BL/6J mice were treated (0.2 mg/mL in
drinking water, n=6-12) from gestational day 12.5 to 18.5. Measures of pup growth, including
body weight, crown/rump length, and abdominal circumference, were reduced in COMT(-/-) mice; this was normalized
after treatment with
Sildenafil. COMT(-/-) mice also demonstrated abnormal umbilical Doppler waveforms, including reverse arterial blood flow velocity. This was normalized
after treatment with
Sildenafil. Abnormal uterine artery Doppler waveforms were not demonstrated in COMT(-/-) mice, although ex vivo responses of uterine arteries to
phenylephrine were increased; moreover, treatment with
Sildenafil did improve ex vivo sensitivity to an endothelium-dependent
vasodilator. The data presented here demonstrate that
Sildenafil can rescue pup growth and improve abnormal umbilical Doppler waveforms, providing support for a potential new therapeutic strategy targeting
fetal growth restriction.