Human Reproduction Update Advance Access published online on November 19, 2009
Human Reproduction Update, doi:10.1093/humupd/dmp046
Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy
1 Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA 5005, Australia 2 Animal and Agricultural Science, University of Adelaide, Roseworthy, SA 5005, Australia 3 Present address: Mothers and Babies Research Centre, Hunter Medical Research Institute, School of Biomedical Sciences, University of Newcastle, Newcastle, NSW 2310, Australia 4 Present address: Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
To whom correspondence should be addressed at: 5 Correspondence address. E-mail: claire.roberts{at}adelaide.edu.au
In the first trimester the extravillous cytotrophoblast cells occlude the uterine spiral arterioles creating a low oxygen environment early in pregnancy, which is essential for pregnancy success. Paradoxically, shallow trophoblast invasion and defective vascular remodelling of the uterine spiral arteries in the first trimester may result in impaired placental perfusion and chronic placental ischemia and hypoxia later in gestation leading to adverse pregnancy outcomes. The hypoxia inducible factors (HIFs) are key mediators of the response to low oxygen. We aimed to elucidate mechanisms of regulation of HIFs and the role these may play in the control of placental differentiation, growth and function in both normal and pathological pregnancies. The Pubmed database was consulted for identification of the most relevant published articles. Search terms used were oxygen, placenta, trophoblast, pregnancy, HIF and hypoxia. The HIFs are able to function throughout all aspects of normal and abnormal placental differentiation, growth and function; during the first trimester (physiologically low oxygen), during mid-late gestation (where there is adequate supply of blood and oxygen to the placenta) and in pathological pregnancies complicated by placental hypoxia/ischemia. During normal pregnancy HIFs may respond to complex alterations in oxygen, hormones, cytokines and growth factors to regulate placental invasion, differentiation, transport and vascularization. In the ever-changing environment created during pregnancy, the HIFs appear to act as key mediators of placental development and function and thereby are likely to be important contributors to both normal and adverse pregnancy outcomes.
Key words: oxygen / hypoxia / placenta / hypoxia inducible factor / trophoblast
Received on January 19, 2009; revised August 31, 2009; accepted on September 28, 2009