Altered placental function of 11beta-hydroxysteroid dehydrogenase 2 knockout mice.
Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal "programming" of adult cardiometabolic and neuropsychiatric disorders. Regulation of fetal glucocorticoid exposure is achieved by the placental glucocorticoid "barrier," which involves glucocorticoid inactivation within the labyrinth zone of the murine placenta by 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2). Thus, the absence of placental 11beta-HSD2 may impact on fetal and placental development. The current study investigated transport of amino acids and glucose, key factors required for fetal growth, and vascular development in placentas from 11beta-HSD2(+/+), (+/-), and (-/-) fetuses derived from 11beta-HSD2(+/-) matings. At embryonic d 15 (E15) (term = E19), 11beta-HSD2(-/-) fetal weight was maintained in comparison to 11beta-HSD2(+/+) fetuses. The maintenance of 11beta-HSD2(-/-) fetal weight occurred despite a reduction in placental weight, suggesting that compensatory changes occur in the placenta to maintain function. However, by E18, 11beta-HSD2(-/-) fetal and placental weights were both reduced. Transport studies revealed up-regulation of placental amino acid transport to 11beta-HSD2(-/-) offspring at E15, coinciding with an increase in the expression of the amino acid transporters. Furthermore, at E18, placental glucose transport to 11beta-HSD2(-/-) offspring was markedly reduced, correlating with lower fetal weight and a decrease in glucose transporter 3 expression. Stereological analyses of the labyrinth zone of the placenta revealed that the reduction in placental weight at E18 was associated with restriction of the normal increase in fetal vessel density over the final third of pregnancy. Our data suggest that restriction of fetal growth in 11beta-HSD2(-/-) mice is mediated, at least in part, via altered placental transport of nutrients and reduction in placental vascularization.
Wyrwoll
Caitlin S
CS
Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, Edinburgh, United Kingdom. cwyrwoll@staffmail.ed.ac.uk
Seckl
Jonathan R
JR
Holmes
Megan C
MC
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000473:pathology; D020567:Fetal Weight / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000235:genetics; D010920:Placenta / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010922:Placenta Diseases / Q000235:genetics* / Q000503:physiopathology; D021041:Placental Circulation / Q000235:genetics; D011247:Pregnancy
D000596:Amino Acids; D001786:Blood Glucose; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D005947:Glucose