Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy

Abstract

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.

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

“…In particular, EPAS1 plays very important, if still poorly understood, roles in both placental and embryonic development (51)(52)(53)(54) and possibly also in the pathogenesis of fetal growth restriction (55). It is well recognized that reproductive success is more difficult at high altitude than at low altitude, and more difficult for nonnatives than natives (6).…”

Effects of oxygen tension and IGF-I on HIF-1α protein expression in mouse blastocysts

“…The α-subunit is hydroxylated at conserved prolyl and asparaginyl residues and targeted for degradation by the von Hippel-Lindau (VHL) ubiquitin E3 ligase complex under normal oxygen conditions. In response to low levels of oxygen, HIF-1α becomes activated and dimerizes with a constitutively expressed HIF-1β, and the complex binds to cis-acting hypoxia response elements in the promoter of target genes, which eventually regulates many cellular activities involved in oxygen homeostasis [3,4,11,[29][30][31]. Consistent with this, Harvey [7,32] suggested that HIFs may be involved in molecular mechanisms which respond to changes in oxygen status during embryo development by expressing genes of HIF-1α, -2α, and -1β subunits in mouse and bovine blastocysts.…”

“…Wenger [34] reported that in vitro functional similarities between HIF-1α and HIF-2α exist in genomic organization, modular protein structure, hypoxic protein stabilization, heterodimerization, DNA binding, and the transactivation function of reporter genes. Furthermore, Pringle et al [4] reviewed that HIF-2α protein levels are increased in a number of endothelial cell lines under mild hypoxia (5 % oxygen tension) and continue to increase with time, thereby playing an important role in mediating effects on gene expression under conditions of prolonged exposure to low oxygen. Therefore, additional studies should be conducted to clarify HIF-2α protein expression as an oxygen mediator in response to chronic hypoxia.…”

“…HIF consists of two subunits HIF-1α and HIF-1β, forming a heterodimer. HIF has been reported to be an essential mediator of transcriptional and/or metabolic responses to both acute and chronic hypoxia in various cell types [3][4][5][6]. In most IVF clinics, embryos are routinely cultured under 5 % oxygen concentration for 3-6 days, which represents the state of chronic hypoxia.…”

“…On the other hand, HIF-1α protein expression can also be induced by a variety of stimuli other than hypoxia, including hormones, cytokines, and growth factors [4]. In vascular smooth muscle cells, HIF-1α protein levels are strongly increased under normoxic conditions when cells are stimulated with angiotensin II (Ang II), thrombin, and platelet derived growth factor (PDGF) [10].…”