title: Inhibition of human placental endothelial cell proliferation and angiogenesis by netrin-4.
abstract: BACKGROUND
  Netrin-4 is a secreted member of the laminin-related protein family, known to be involved in axonal guidance and endothelial cell survival, proliferation, and migration. We have recently reported the cellular localization of netrin-4 and its receptor neogenin in human first trimester and term placenta. A strong expression of netrin-4 was observed in trophoblast and in endothelial cells, suggesting a potential role of this protein in placental angiogenesis. In relation to human pregnancy, it has been reported that circulating netrin-4 were increased in fetal umbilical cord blood of intrauterine growth restriction IUGR compared to normal pregnancy suggesting an adverse effect of this protein on placental and fetal development. The aim of this study was to determine the role of netrin-4 in placental angiogenesis.
  
  
  METHODS
  The effects of netrin-4 on proliferation, migration, tube-like organization, and spheroid sprouting of human placental microvascular endothelial cells (HPEC) were studied.
  
  
  RESULTS
  We demonstrated that netrin-4 inhibits HPEC proliferation, tube-like formation, migration and spheroid sprouting, suggesting a direct role of netrin-4 in the regulation of intra-villus angiogenesis.
  
  
  CONCLUSIONS
  This is the first report of an anti-angiogenic activity of netrin-4 in human placenta. This study brings new insights into netrin-4 roles in placental angiogenesis and suggests possible involvements of netrin-4 in angiogenesis-related pathologies such as IUGR.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1179, Montigny Le Bretonneux, France; Université de Versailles Saint Quentin, En Yvelines, France. Electronic address: mbarka.dakouane-giudicelli@uvsq.fr.
authors.forename: M
authors.initials: M
authors.lastname: Dakouane-Giudicelli
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, 38000 Grenoble, France; Commissariat à l'Energie Atomique (CEA), iRTSV-Biology of Cancer and Infection, Grenoble, France; Centre Hospitalier Universitaire de Grenoble, Hôpital Couple-Enfant, Centre Clinique et Biologique d'Assistance Médicale à la Procréation, 38700 La Tronche, France.
authors.forename: S
authors.initials: S
authors.lastname: Brouillet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France.
authors.forename: W
authors.initials: W
authors.lastname: Traboulsi
authors.affiliation: Université de Versailles Saint Quentin, En Yvelines, France.
authors.forename: A
authors.initials: A
authors.lastname: Torre
authors.affiliation: Université de Versailles Saint Quentin, En Yvelines, France.
authors.forename: G
authors.initials: G
authors.lastname: Vallat
authors.affiliation: Université de Versailles Saint Quentin, En Yvelines, France.
authors.forename: S
authors.initials: S
authors.lastname: Si Nacer
authors.affiliation: Université de Versailles Saint Quentin, En Yvelines, France.
authors.forename: M
authors.initials: M
authors.lastname: Vallée
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, 38000 Grenoble, France; Commissariat à l'Energie Atomique (CEA), iRTSV-Biology of Cancer and Infection, Grenoble, France.
authors.forename: J J
authors.initials: JJ
authors.lastname: Feige
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; Université Grenoble-Alpes, 38000 Grenoble, France; Commissariat à l'Energie Atomique (CEA), iRTSV-Biology of Cancer and Infection, Grenoble, France.
authors.forename: N
authors.initials: N
authors.lastname: Alfaidy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1179, Montigny Le Bretonneux, France; Université de Versailles Saint Quentin, En Yvelines, France; AP-HP Hopital Ambroise Paré, Boulogne-Billancourt, France.
authors.forename: P
authors.initials: P
authors.lastname: de Mazancourt
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D018919:Neovascularization, Physiologic; D009414:Nerve Growth Factors / Q000502:physiology*; D000075385:Netrins; D018874:Spheroids, Cellular / Q000502:physiology
chemical_list: C498815:NTN4 protein, human; D009414:Nerve Growth Factors; D000075385:Netrins
keywords: Angiogenesis; HPEC; Human placenta; Netrin-4; Placenta