title: Oxygen Sensitivity of Placental Trophoblast Connexins 43 and 46: A Role in Preeclampsia?
abstract: Several gap junction connexins have been shown to be essential for appropriate placental development and function. It is known that the expression and distribution of connexins change in response to environmental oxygen levels. The placenta develops under various oxygen levels, beginning at a low oxygen tension of approximately 2% and increasing to a tension of 8% after the onset of the uteroplacental circulation. Moreover, it has been shown that during preeclampsia (PE) placentas are subjected to chronic hypoxia. Therefore, we investigated oxygen sensitivity of placental connexins 43 and 46. Using the trophoblast cell line Jar, we demonstrated that the expression of connexin43 increased during acute hypoxia but decreased during chronic hypoxia. Chronic hypoxia resulted in the translocation of connexin43 from the membrane to the cytoplasm and in a reduction in its communication properties. In contrast, the expression of connexin46 was down-regulated during chronic hypoxia and was translocated from perinuclear areas to the cell membrane. Hypoxia-inducible factor (HIF) knockdown showed that the translocation of connexin43 but not that of connexin46 was HIF-2α dependent and was mediated by phosphoinositide 3-kinase. The up-regulation of connexin43 in combination with the down-regulation of connexin46 was confirmed in placental explants cultivated under low oxygen and in placentas with early-onset PE. Taken together, in Jar cells, placental connexins 43 and 46 are regulated during periods of low oxygen in opposite manners. The oxygen sensing of connexins in the trophoblast may play a role in physiological and pathophysiological oxygen conditions and thus may contribute to PE.
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.|Institute of Physiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Otto
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.|Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gellhaus
authors.affiliation: Institute of Physiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Navina
authors.initials: N
authors.lastname: Lüschen
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Scheidler
authors.affiliation: Department of Pediatrics I, Neonatology, University Hospital Essen, Essen, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
authors.affiliation: Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dunk
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Wolf
authors.affiliation: Institute of Cell Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Lennartz
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Köninger
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum Duisburg, Duisburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.affiliation: Institute of Physiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Winterhager
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D018031:Connexin 43 / Q000096:biosynthesis* / Q000378:metabolism; D017630:Connexins / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics; D010100:Oxygen / Q000378:metabolism*; D010929:Placentation; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D018031:Connexin 43; D017630:Connexins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C082917:GJA3 protein, human; D010100:Oxygen
keywords: CONNEXIN43; CONNEXIN46; HIF; PREECLAMPSIA; TROPHOBLAST