title: Compensatory feto-placental upregulation of the nitric oxide system during fetal growth restriction.
abstract: BACKGROUND
  Fetal Growth Restriction is often associated with a feto-placental vascular dysfunction conceivably involving endothelial cells. Our study aimed to verify this pathogenic role for feto-placental endothelial cells and, coincidentally, demonstrate any abnormality in the nitric oxide system.
  
  
  METHODS
  Prenatal assessment of feto-placental vascular function was combined with measurement of nitric oxide (in the form of S-nitrosohemoglobin) and its nitrite byproduct, and of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. Umbilical vein endothelial cells were also harvested to determine their gene profile. The study comprised term pregnancies with normal (n = 40) or small-for-gestational-age (n = 20) newborns, small-for-gestational-age preterm pregnancies (n = 15), and bi-chorial, bi-amniotic twin pregnancies with discordant fetal growth (n = 12).
  
  
  RESULTS
  Umbilical blood nitrite (p<0.001) and S-nitrosohemoglobin (p = 0.02) rose with fetal growth restriction while asymmetric dimethylarginine decreased (p = 0.003). Nitrite rise coincided with an abnormal Doppler profile from umbilical arteries. Fetal growth restriction umbilical vein endothelial cells produced more nitrite and also exhibited reciprocal changes in vasodilator (upwards) and vasoconstrictor (downwards) transcripts. Elevation in blood nitrite and S-nitrosohemoglobin persisted postnatally in the fetal growth restriction offspring.
  
  
  CONCLUSIONS
  Fetal growth restriction is typified by increased nitric oxide production during pregnancy and after birth. This response is viewed as an adaptative event to sustain placental blood flow. However, its occurrence may modify the endothelial phenotype and may ultimately represent an element of risk for cardiovascular disease in adult life.
authors.affiliation: Division of Obstetrics and Gynecology, Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pisaneschi
authors.forename: Francesca A L
authors.initials: FA
authors.lastname: Strigini
authors.forename: Angel M
authors.initials: AM
authors.lastname: Sanchez
authors.forename: Silvia
authors.initials: S
authors.lastname: Begliuomini
authors.forename: Elena
authors.initials: E
authors.lastname: Casarosa
authors.forename: Andrea
authors.initials: A
authors.lastname: Ripoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghirri
authors.forename: Antonio
authors.initials: A
authors.lastname: Boldrini
authors.forename: Bruno
authors.initials: B
authors.lastname: Fink
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Genazzani
authors.forename: Flavio
authors.initials: F
authors.lastname: Coceani
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
mesh_terms: D000222:Adaptation, Physiological; D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D005317:Fetal Growth Retardation / Q000097:blood* / Q000000981:diagnostic imaging / Q000235:genetics; D005333:Fetus; D020869:Gene Expression Profiling; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014463:Ultrasonography; D014469:Umbilical Arteries / Q000000981:diagnostic imaging / Q000378:metabolism; D014471:Umbilical Veins / Q000000981:diagnostic imaging / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D006454:Hemoglobins; D009573:Nitrites; C103574:S-nitrosohemoglobin; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III