title: Sildenafil Therapy Normalizes the Aberrant Metabolomic Profile in the Comt(-/-) Mouse Model of Preeclampsia/Fetal Growth Restriction.
abstract: Preeclampsia (PE) and fetal growth restriction (FGR) are serious complications of pregnancy, associated with greatly increased risk of maternal and perinatal morbidity and mortality. These complications are difficult to diagnose and no curative treatments are available. We hypothesized that the metabolomic signature of two models of disease, catechol-O-methyl transferase (COMT(-/-)) and endothelial nitric oxide synthase (Nos3(-/-)) knockout mice, would be significantly different from control C57BL/6J mice. Further, we hypothesised that any differences in COMT(-/-) mice would be resolved following treatment with Sildenafil, a treatment which rescues fetal growth. Targeted, quantitative comparisons of serum metabolic profiles of pregnant Nos3(-/-), COMT(-/-) and C57BL/6J mice were made using a kit from BIOCRATES. Significant differences in 4 metabolites were observed between Nos3(-/-) and C57BL/6J mice (p < 0.05) and in 18 metabolites between C57BL/6J and COMT(-/-) mice (p < 0.05). Following treatment with Sildenafil, only 5 of the 18 previously identified differences in metabolites (p < 0.05) remained in COMT(-/-) mice. Metabolomic profiling of mouse models is possible, producing signatures that are clearly different from control animals. A potential new treatment, Sildenafil, is able to normalize the aberrant metabolomic profile in COMT(-/-) mice; as this treatment moves into clinical trials, this information may assist in assessing possible mechanisms of action.
authors.affiliation: Liggins Institute, University of Auckland, New Zealand.|Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Stanley
authors.affiliation: Liggins Institute, University of Auckland, New Zealand.
authors.forename: Karolina
authors.initials: K
authors.lastname: Sulek
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Irene J
authors.initials: IJ
authors.lastname: Andersson
authors.affiliation: Women and Children's Health Research Institute, University of Alberta, Edmonton, Canada.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.affiliation: Anu Research Centre, University College Cork, Ireland.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Kenny
authors.affiliation: Maternal &Fetal Health Research Centre, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK.
authors.forename: Colin P
authors.initials: CP
authors.lastname: Sibley
authors.affiliation: The Metabolomics Innovation Centre (TMIC), University of Alberta, Edmonton, Canada.
authors.forename: Rupasri
authors.initials: R
authors.lastname: Mandal
authors.affiliation: The Metabolomics Innovation Centre (TMIC), University of Alberta, Edmonton, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Wishart
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: David I
authors.initials: DI
authors.lastname: Broadhurst
authors.affiliation: Liggins Institute, University of Auckland, New Zealand.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Baker
mesh_terms: D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D011225:Pre-Eclampsia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D000068677:Sildenafil Citrate / Q000494:pharmacology*
chemical_list: D000068677:Sildenafil Citrate; D002394:Catechol O-Methyltransferase