title: Sildenafil citrate increases fetal weight in a mouse model of fetal growth restriction with a normal vascular phenotype.
abstract: Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5(th) centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5(th) centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. (14)C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR.
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester, United Kingdom ; Manchester Academic Health Science Centre, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Mark Robert
authors.initials: MR
authors.lastname: Dilworth
authors.forename: Irene
authors.initials: I
authors.lastname: Andersson
authors.forename: Lewis James
authors.initials: LJ
authors.lastname: Renshall
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cowley
authors.forename: Philip
authors.initials: P
authors.lastname: Baker
authors.forename: Susan
authors.initials: S
authors.lastname: Greenwood
authors.forename: Colin Peter
authors.initials: CP
authors.lastname: Sibley
authors.forename: Mark
authors.initials: M
authors.lastname: Wareing
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000188:drug therapy* / Q000378:metabolism; D020567:Fetal Weight / Q000187:drug effects*; D005333:Fetus / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010920:Placenta / Q000098:blood supply / Q000378:metabolism; D011247:Pregnancy; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014469:Umbilical Arteries / Q000378:metabolism; D055988:Uterine Artery / Q000378:metabolism*
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D007335:Insulin-Like Growth Factor II; D000068677:Sildenafil Citrate