title: Sildenafil citrate rescues fetal growth in the catechol-O-methyl transferase knockout mouse model.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada. jlstanle@ualberta.ca
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Stanley
authors.forename: Irene J
authors.initials: IJ
authors.lastname: Andersson
authors.forename: Rajan
authors.initials: R
authors.lastname: Poudel
authors.forename: Christian F
authors.initials: CF
authors.lastname: Rueda-Clausen
authors.forename: Colin P
authors.initials: CP
authors.lastname: Sibley
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.forename: Philip N
authors.initials: PN
authors.lastname: Baker
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000000981:diagnostic imaging / Q000503:physiopathology* / Q000517:prevention & control*; D006973:Hypertension / Q000150:complications / Q000175:diagnosis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009215:Myometrium / Q000098:blood supply*; D010879:Piperazines / Q000008:administration & dosage*; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000503:physiopathology; D011247:Pregnancy; D011507:Proteinuria / Q000150:complications / Q000175:diagnosis; D011687:Purines / Q000008:administration & dosage; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D018608:Ultrasonography, Doppler; D014469:Umbilical Arteries / Q000000981:diagnostic imaging / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D002394:Catechol O-Methyltransferase