title: Enhancement of the HIF-1α/15-LO/15-HETE axis promotes hypoxia-induced endothelial proliferation in preeclamptic pregnancy.
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.
authors.affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Yuan
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Ran
authors.affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Hongqi Hospital of Mudanjiang Medical College, Mudanjiang, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Peiling
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000328:Adult; D001093:Arachidonate 15-Lipoxygenase / Q000097:blood / Q000378:metabolism*; D002453:Cell Cycle; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D014470:Umbilical Cord / Q000378:metabolism
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D001093:Arachidonate 15-Lipoxygenase