Document Detail

eNOS knockout mouse as a model of fetal growth restriction with an impaired uterine artery function and placental transport phenotype.
MedLine Citation:
PMID:  22552791     Owner:  NLM     Status:  MEDLINE    
Fetal growth restriction (FGR) is the inability of a fetus to reach its genetically predetermined growth potential. In the absence of a genetic anomaly or maternal undernutrition, FGR is attributable to "placental insufficiency": inappropriate maternal/fetal blood flow, reduced nutrient transport or morphological abnormalities of the placenta (e.g., altered barrier thickness). It is not known whether these diverse factors act singly, or in combination, having additive effects that may lead to greater FGR severity. We suggest that multiplicity of such dysfunction might underlie the diverse FGR phenotypes seen in humans. Pregnant endothelial nitric oxide synthase knockout (eNOS(-/-)) dams exhibit dysregulated vascular adaptations to pregnancy, and eNOS(-/-) fetuses of such dams display FGR. We investigated the hypothesis that both altered vascular function and placental nutrient transport contribute to the FGR phenotype. eNOS(-/-) dams were hypertensive prior to and during pregnancy and at embryonic day (E) 18.5 were proteinuric. Isolated uterine artery constriction was significantly increased, and endothelium-dependent relaxation significantly reduced, compared with wild-type (WT) mice. eNOS(-/-) fetal weight and abdominal circumference were significantly reduced compared with WT. Unidirectional maternofetal (14)C-methylaminoisobutyric acid (MeAIB) clearance and sodium-dependent (14)C-MeAIB uptake into mouse placental vesicles were both significantly lower in eNOS(-/-) fetuses, indicating diminished placental nutrient transport. eNOS(-/-) mouse placentas demonstrated increased hypoxia at E17.5, with elevated superoxide compared with WT. We propose that aberrant uterine artery reactivity in eNOS(-/-) mice promotes placental hypoxia with free radical formation, reducing placental nutrient transport capacity and fetal growth. We further postulate that this mouse model demonstrates "uteroplacental hypoxia," providing a new framework for understanding the etiology of FGR in human pregnancy.
Laura C Kusinski; Joanna L Stanley; Mark R Dilworth; Cassandra J Hirt; Irene J Andersson; Lewis J Renshall; Bernadette C Baker; Philip N Baker; Colin P Sibley; Mark Wareing; Jocelyn D Glazier
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-02
Journal Detail:
Title:  American journal of physiology. Regulatory, integrative and comparative physiology     Volume:  303     ISSN:  1522-1490     ISO Abbreviation:  Am. J. Physiol. Regul. Integr. Comp. Physiol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-09-18     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  R86-93     Citation Subset:  IM    
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MeSH Terms
Amino Acid Transport System A / metabolism
Biological Transport / physiology
Blood Pressure / physiology
Fetal Growth Retardation / metabolism,  physiopathology*
Fetal Weight / physiology
Mice, Inbred C57BL
Mice, Knockout
Models, Animal*
Nitric Oxide Synthase Type III / deficiency*,  genetics
Placenta / metabolism,  physiopathology*
Proteinuria / metabolism,  physiopathology
Superoxides / metabolism
Uterine Artery / physiopathology*
Grant Support
92495//Medical Research Council; G0802770//Medical Research Council; //Biotechnology and Biological Sciences Research Council
Reg. No./Substance:
0/Amino Acid Transport System A; 11062-77-4/Superoxides; EC Oxide Synthase Type III

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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