Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1.
Elevated expression of soluble vascular endothelial growth factor receptor-1 (sFlt-1) in preeclampsia plays a major role in the pathogenesis of this serious disorder of human pregnancy. Although reduced placental oxygenation is thought to be involved in the pathogenesis of preeclampsia, it is unclear how oxygen regulates placental sFlt-1 expression. The aims herein were to investigate sFlt-1 expression in in vivo and in vitro physiological and pathological models of human placental hypoxia and to understand the role of hypoxia inducible factor-1 (HIF-1) in regulating the expression of this molecule. sFlt-1 expression in placental villi was significantly increased under physiological low oxygen conditions in early first-trimester and in high-altitude placentae, as well as in pathological low oxygen conditions, such as preeclampsia. In high-altitude and in preeclamptic tissue, sFlt-1 localized within villi to perivascular regions, the syncytiotrophoblast layer, and syncytial knots. In first-trimester villous explants, low oxygen, but not hypoxia-reoxygenation (HR), increased sFlt-1 expression. Moreover, exposure of villous explants to dimethyloxalyl-glycin, a pharmacological inhibitor of prolyl-hydroxylases, which mimics hypoxia by increasing HIF-1alpha stability, increased sFlt-1 expression. Conversely, HIF-1alpha knockdown using antisense oligonucleotides, decreased sFlt-1 expression. In conclusion, placental sFlt-1 expression is increased by both physiologically and pathologically low levels of oxygen. This oxygen-induced effect is mediated via the transcription factor HIF-1. Low oxygen levels, as opposed to intermittent oxygen tension (HR) changes, play an important role in regulating sFlt-1 expression in the developing human placenta and hence may contribute to the development of preeclampsia.
Nevo
Ori
O
Mount Sinai Hospital, Department of Obstetrics, University of Toronto, Canada.
Soleymanlou
Nima
N
Wu
Yuan
Y
Xu
Jing
J
Kingdom
John
J
Many
Ariel
A
Zamudio
Stacy
S
Caniggia
Isabella
I
D000328:Adult; D000531:Altitude; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D066298:In Vitro Techniques; D010100:Oxygen / Q000494:pharmacology; D010920:Placenta / Q000166:cytology / Q000502:physiology*; D011225:Pre-Eclampsia / Q000378:metabolism / Q000503:physiopathology*; D011247:Pregnancy; D012995:Solubility; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D010100:Oxygen