title: Role of extracellular signal-regulated kinase and AKT cascades in regulating hypoxia-induced angiogenic factors produced by a trophoblast-derived cell line.
abstract: During human pregnancy, trophoblasts play an important role in embryo implantation and placental development. Cytotrophoblast cells invade the uterine spiral arteries and differentiate into extravillous trophoblasts, resulting in the remodeling of the uterine vessels and fetoplacental vasculature. During early pregnancy, a physiologically hypoxic environment induces the production of angiogenic factors, such as vascular endothelial growth factor (VEGF), which are suggested to locally control the vascular remodeling. Endoglin, a cell-surface coreceptor for transforming growth factor-beta1, is highly expressed in endothelial cells and syncytiotrophoblasts, and can be associated with endothelial nitric oxide synthase and vascular homeostasis. Several studies have recently suggested that some pregnancy-related complications, such as preeclampsia, have their origins early in pregnancy as a result of abnormalities in implantation and placental development. Although angiogenic factors are recognized as key molecules in placental development, little is known about the mechanism(s) of their regulation in trophoblasts. In this study, we elucidated the mechanisms underlying the regulation of VEGF and endoglin production under hypoxic conditions in the trophoblast-derived cell line, BeWo. We evaluated the role of the AKT-MTOR cascade and ERK kinase in the expression of VEGF and endoglin in response to hypoxia using various kinase inhibitors and small interfering RNA targeted against hypoxia-inducible factor (HIF)-1alpha (listed as HIF1A in Hugo Database). Our results suggest that both the phosphatidylinositol 3-kinase-AKT-MTOR-HIF-1alpha and ERK-HIF-1alpha signaling pathways are crucial for increasing VEGF and endoglin expression in response to hypoxia in BeWo cells.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki-City, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujita
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanabe
authors.forename: Tatsuharu
authors.initials: T
authors.lastname: Sekijima
authors.forename: Hekiko
authors.initials: H
authors.lastname: Soen
authors.forename: Keijirou
authors.initials: K
authors.lastname: Narahara
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Terai
authors.forename: Hideki
authors.initials: H
authors.lastname: Kamegai
authors.forename: Masahide
authors.initials: M
authors.lastname: Ohmichi
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D002822:Choriocarcinoma; D000071063:Endoglin; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D010100:Oxygen; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014162:Transfection; D014327:Trophoblasts / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D043925:Angiogenesis Inducing Agents; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D010100:Oxygen