Abstract
Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1α and HIF-2α are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-α-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel–Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-α-subunits is defective. This is associated with enhanced VHL/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases.
Highlights
Preeclampsia (PE) and intrauterine growth restriction (IUGR) are common and potentially serious complications of pregnancy
hypoxia-inducible factor (HIF)-1α and HIF-2α Are Elevated in Early-Onset IUGR and PE Placentae
Abnormal placentation is common in both IUGR and PE
Summary
Preeclampsia (PE) and intrauterine growth restriction (IUGR) are common and potentially serious complications of pregnancy. Early-onset PE, often accompanied by IUGR, is a multi-organ disorder characterised by maternal endothelial dysfunction, hypertension, and proteinuria [3] Despite both conditions showing the constant pathological feature of abnormal placentation, the mother is only affected in PE. Placental expression of hypoxia-responsive genes (including hypoxia-inducible factor (HIF)-1α, HIF-2α) is increased in PE compared with normal controls [6–9]. The inhibition of hydroxylation results in the dimerization of HIF-α-subunit with HIF-1β and enhanced transcription of the genes containing hypoxia-response elements in the promoter [17]. The HIF-α-subunits were transcriptionally active as the level of target gene sFlt-1 was enhanced in both pathologies This was despite elevated expression of PHD2 and 3 and factor inhibiting HIF (FIH) and no deficiency in Sprouty or VHL expression. A lack of substrate recognition by the ubiquitin ligase complex seems to be a central driver of the pathogenesis of these disorders
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