Abstract
Preeclampsia (PE) is an extremely serious condition in pregnant women and the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiological factors of this disorder remain elusive. The increased release of 15-hydroxyeicosatetraenoic acid (15-HETE) in the placenta of preeclamptic patients has been studied, but its exact role in PE pathogenesis remains unknown. Mounting evidence shows that PE is associated with placental hypoxia, impaired placental angiogenesis, and endothelial dysfunction. In this study, we confirmed the upregulated expression of hypoxia-inducible factor 1α (HIF-1α) and 15-lipoxygenase-1/2 (15-LO-1/2) in patients with PE. Production of the arachidonic acid metabolite, 15-HETE, also increased in the preeclamptic placenta, which suggests enhanced activation of the HIF-1α–15-LO–15-HETE axis. Furthermore, this study is the first to show that the umbilical cord of preeclamptic women contains significantly higher serum concentrations of 15-HETE than that of healthy pregnant women. The results also show that expression of 15-LO-1/2 is upregulated in both human umbilical vein endothelial cells (HUVECs) collected from preeclamptic women and in those cultured under hypoxic conditions. Exogenous 15-HETE promotes the migration of HUVECs and in vitro tube formation and promotes cell cycle progression from the G0/G1 phase to the G2/M + S phase, whereas the 15-LO inhibitor, NDGA, suppresses these effects. The HIF-1α/15-LO/15-HETE pathway is therefore significantly associated within the pathology of PE.
Highlights
Preeclampsia (PE) is a pregnancy-specific syndrome that seriously threatens the health and safety of mothers and children, affecting 3% to 5% of all pregnancies [1]
A similar increase in the expression of hypoxiainducible factor 1a (HIF-1a) was observed in preeclamptic placentas, compared to that seen in normal tissue (Figure 1C)
Early intervention may be beneficial for patients with PE, novel insights into the mechanisms underlying PE will undoubtedly deepen our understanding of its pathogenesis and provide more rational treatment strategies [25]
Summary
Preeclampsia (PE) is a pregnancy-specific syndrome that seriously threatens the health and safety of mothers and children, affecting 3% to 5% of all pregnancies [1]. Reduced placental perfusion and ischemia/hypoxia caused by impaired trophoblast invasion may induce the placenta to release various vasomotor regulatory factors, causing various angiogenic abnormalities and alterations in circulating angiogenic factors in the maternal vasculature [5,6]. Significant morphologic changes occur in the villous architecture of the preeclamptic placenta [7]. The placentas of women with PE have been found to have a greater degree of villous capillary branching than those from healthy pregnant women, which suggests dysregulation of angiogenesis [8]. Oxygen tension is a critical factor in the regulation of angiogenesis [9]. Placental development during normal pregnancy takes place within a relatively low oxygen environment, and this physiologic hypoxia is critical for early placental development and angiogenesis [10].
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