Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development

Abstract

Early human placental and embryonic development occurs in a physiologically low oxygen environment supported by histiotrophic secretions from endometrial glands. In this study, we compare the placental metabolomic profile in the first, second and third trimesters to determine whether the energy demands are adequately met in the first trimester. We investigated whether hypoxia-inducible factors, HIF-1α and/or HIF-2α, might regulate transcription during the first trimester. First and second trimester tissue was collected using a chorionic villus sampling-like (CVS) technique. Part of each villus sample was frozen immediately and the remainder cultured under 2 or 21% O2 ± 1 mM H2O2, and ±the p38 MAPK pathway inhibitor, PD169316. Levels of HIF-1α were assessed by western blotting and VEGFA, PlGF and GLUT3 transcripts were quantified by RT–PCR. Term samples were collected from normal elective Caesarean deliveries. There were no significant differences in concentrations of ADP, NAD+, lactate, and glucose, and in the ATP/ADP ratio, across gestational age. Neither HIF-1α nor HIF-2α could be detected in time-zero CVS samples. However, culture under any condition (2 or 21% O2 ± 1 mM H2O2) increased HIF-1α and HIF-2α. HIF-1α and HIF-2α were additionally detected in specimens retrieved after curettage. HIF-1α stabilization was accompanied by significant increases in VEGFA and GLUT3 and a decrease in PlGF mRNAs. These effects were suppressed by PD169316. In conclusion, our data suggest that first trimester placental tissues are not energetically compromised, and that HIF-1α is unlikely to play an appreciable role in regulating transcriptional activity under steady-state conditions in vivo. However, the pathway may be activated by stress conditions.

Upregulation and release of soluble fms‐like tyrosine kinase receptor 1 mediated by complement activation in human syncytiotrophoblast cells

“…33,34 Although oxygen tension in first trimester human placenta is low (hypoxic), it is now well accepted as normal physiological state which is required for normal placental development. 35 In vivo studies relating placental hypoxia to antiangiogenic milieu and eventually preeclampsia heavily rely on increased expression of hypoxia response element HIF1α. Recent data suggest that HIF1α was also reactive to autoantibodies such as anti-angiotensin II type I receptor and various stressors through stress kinases.…”

“…Recent data suggest that HIF1α was also reactive to autoantibodies such as anti-angiotensin II type I receptor and various stressors through stress kinases. 36, 35 Further, HIF1α could modulate angiogenic factors independent of oxygen levels. 35 Nevertheless, immunological factors may be upstream to the development of placental hypoxia.…”

Decreased ATP production and myocardial contractile reserve in metabolic heart disease

“…Total maximal CK activity was measured using a colorimetric Creatine Kinase Assay Kit according to the manufacturer’s protocol (Abcam, Cambridge, MA) [25]. Briefly, freshly isolated tissue was homogenized in assay buffer, centrifuged to remove insoluble material, and supernatant was used for activity and immunoblotting.…”

An essay of reflection: Why does preeclampsia exist in humans, and why are there such huge geographical differences in epidemiology?

“…This is in line with the maternal versus placental preeclampsia phenotype (Redman and Sargent, 2007), which clearly makes the point that the lack of spiral artery remodeling is a major but certainly not mandatory requirement for arriving at the maternal phenotype. The actual maternal disease relates to what happens in the syncytiotrophoblast with the release of anti-angiogenic factors, microparticles (exosomes -"little cluster bombs") (Redman et al, 2012), and apparently also the release of IPG-P. All of this may be related to syncytiotrophoblast ER stress (Cindrova- Davies et al, 2015). This concept allows a more logical paradigm that dictates that all factors causing ER stress (ischemia/reperfusion due to lack of remodeling, maternal comorbidities, some infections, getting too far post-term, etc.)…”