A Tarrade1, E Lecarpentier2, S Gil3, O Morel4, N Zahr5, M Dahirel6, V Tsatsaris7, P Chavatte-Palmer6. 1. INRA, UMR1198 Biologie du Développement et Reproduction, 78352 Jouy-en-Josas, France/ENVA, 94700 Maisons-Alfort, France; Fondation PremUp, 4 av. de l'Observatoire, 75006 Paris, France. Electronic address: anne.tarrade@jouy.inra.fr. 2. INRA, UMR1198 Biologie du Développement et Reproduction, 78352 Jouy-en-Josas, France/ENVA, 94700 Maisons-Alfort, France; Fondation PremUp, 4 av. de l'Observatoire, 75006 Paris, France; INSERM U767, Université Paris-Descartes, 4 av. de l'Observatoire, 75006 Paris, France. 3. Fondation PremUp, 4 av. de l'Observatoire, 75006 Paris, France; INSERM U767, Université Paris-Descartes, 4 av. de l'Observatoire, 75006 Paris, France. 4. INRA, UMR1198 Biologie du Développement et Reproduction, 78352 Jouy-en-Josas, France/ENVA, 94700 Maisons-Alfort, France; Département d'obstétrique et de gynécologie, Maternité régionale Universitaire de Nancy, Université Nancy I H.Poincaré, Nancy, France. 5. UF pharmacologie et pharmacogénétique, Groupe hospitalier Pitié-Salpêtrière, 75013 Paris, France. 6. INRA, UMR1198 Biologie du Développement et Reproduction, 78352 Jouy-en-Josas, France/ENVA, 94700 Maisons-Alfort, France; Fondation PremUp, 4 av. de l'Observatoire, 75006 Paris, France. 7. Fondation PremUp, 4 av. de l'Observatoire, 75006 Paris, France; INSERM U767, Université Paris-Descartes, 4 av. de l'Observatoire, 75006 Paris, France; Maternité Port-Royal, Hôpital Cochin, APHP, Université Paris-Descartes, Paris, France.
Abstract
OBJECTIVES: We have previously validated the use of L-nitro-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, to induce placental hypoperfusion in a rabbit model. Here, the effects of L-NAME on placental vascularization were explored. Transplacental transfer of L-NAME and/or its active metabolite, NG-nitro-L-arginine (L-NOARG), was evaluated. METHODS: 25 pregnant female rabbits were allocated on day 24 to one of 5 groups: L-NAME groups (31.35, 62.5, 125 and 250 mg/kg/day) or Control group (C). On Day 28, the labyrinthine area was analyzed for stereology and gene expression. L-NAME and L-NOARG were quantified in maternal and fetal blood. RESULTS: The volume density of fetal vessels was significantly decreased in L-NAME (including 62.5-250 mg/kg/day which induced an IUGR) compared to C groups. L-NAME induced an increase of the volume and surface density of the maternal blood space. The trophoblast volume density remained unchanged as well as the surface density of fetal vessels. Relative expression of eNOS, VEGFA, VEGFR-1 and VEGFR-2 in placentas was not affected by 125 mg/kg/day L-NAME treatment, whereas IGF-2 expression was significantly increased in this L-NAME group compared to C. L-NAME was not detected in maternal nor fetal plasma. In contrast, fetal to maternal L-NOARG ratio was 100% in all L-NAME groups. CONCLUSION: These data demonstrate that L-NAME induced placental hypovascularization. The active L-NOARG metabolite is found in maternal and fetal plasma at similar concentrations. This could impact the fetal growth and reduces the interest of this model to study fetal outcomes of placental hypoperfusion.
OBJECTIVES: We have previously validated the use of L-nitro-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, to induce placental hypoperfusion in a rabbit model. Here, the effects of L-NAME on placental vascularization were explored. Transplacental transfer of L-NAME and/or its active metabolite, NG-nitro-L-arginine (L-NOARG), was evaluated. METHODS: 25 pregnant female rabbits were allocated on day 24 to one of 5 groups: L-NAME groups (31.35, 62.5, 125 and 250 mg/kg/day) or Control group (C). On Day 28, the labyrinthine area was analyzed for stereology and gene expression. L-NAME and L-NOARG were quantified in maternal and fetal blood. RESULTS: The volume density of fetal vessels was significantly decreased in L-NAME (including 62.5-250 mg/kg/day which induced an IUGR) compared to C groups. L-NAME induced an increase of the volume and surface density of the maternal blood space. The trophoblast volume density remained unchanged as well as the surface density of fetal vessels. Relative expression of eNOS, VEGFA, VEGFR-1 and VEGFR-2 in placentas was not affected by 125 mg/kg/day L-NAME treatment, whereas IGF-2 expression was significantly increased in this L-NAME group compared to C. L-NAME was not detected in maternal nor fetal plasma. In contrast, fetal to maternal L-NOARG ratio was 100% in all L-NAME groups. CONCLUSION: These data demonstrate that L-NAME induced placental hypovascularization. The active L-NOARG metabolite is found in maternal and fetal plasma at similar concentrations. This could impact the fetal growth and reduces the interest of this model to study fetal outcomes of placental hypoperfusion.
Authors: Jorge Lopez-Tello; Maria Arias-Alvarez; Maria Angeles Jimenez-Martinez; Rosa Maria Garcia-Garcia; Maria Rodriguez; Pedro Luis Lorenzo Gonzalez; Ruben Bermejo-Poza; Antonio Gonzalez-Bulnes; Pilar Garcia Rebollar Journal: PLoS One Date: 2017-01-03 Impact factor: 3.240
Authors: Sarah A Valentino; Anne Tarrade; Josiane Aioun; Eve Mourier; Christophe Richard; Michèle Dahirel; Delphine Rousseau-Ralliard; Natalie Fournier; Marie-Christine Aubrière; Marie-Sylvie Lallemand; Sylvaine Camous; Marine Guinot; Madia Charlier; Etienne Aujean; Hala Al Adhami; Paul H Fokkens; Lydiane Agier; John A Boere; Flemming R Cassee; Rémy Slama; Pascale Chavatte-Palmer Journal: Part Fibre Toxicol Date: 2016-07-26 Impact factor: 9.400