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1 Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, Canada; Departments of Obstetrics and Gynaecology and Physiology, University of Toronto, Toronto, Canada
2 Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, Canada
3 New Jersey Medical School, Newwark, New Jersey, United States
* To whom correspondence should be addressed. E-mail: caniggia{at}mshri.on.ca.
Elevated expression of soluble VEGF receptor-1 (sFlt-1) in preeclampsia plays a major role in the pathogenesis of this serious disorder of human pregnancy. While 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 HIF-1 in regulating the expression of this molecule. sFlt-1 expression in placental villi was significantly increased under physiological low oxygen condition in early first trimester and in high altitude placentae as well as in pathological low oxygen 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 (DMOG), a pharmacological inhibitor of prolyl-hydroxylases, which mimics hypoxia by increasing HIF-1
stability, increased sFlt-1 expression. Conversely, HIF-1 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.
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