M Dakouane-Giudicelli1, S Brouillet2, W Traboulsi3, A Torre4, G Vallat4, S Si Nacer4, M Vallée4, J J Feige5, N Alfaidy5, P de Mazancourt6. 1. 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. 2. 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. 3. Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France. 4. Université de Versailles Saint Quentin, En Yvelines, France. 5. 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. 6. 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.
Abstract
INTRODUCTION: 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. DISCUSSION: 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.
INTRODUCTION: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. DISCUSSION: 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: Catalina P Prieto; María Carolina Ortiz; Andrea Villanueva; Cynthia Villarroel; Sandra S Edwards; Matías Elliott; José Lattus; Sócrates Aedo; Daniel Meza; Pablo Lois; Verónica Palma Journal: Stem Cell Res Ther Date: 2017-02-28 Impact factor: 6.832