title: Sustained Endocrine Gland-Derived Vascular Endothelial Growth Factor Levels Beyond the First Trimester of Pregnancy Display Phenotypic and Functional Changes Associated With the Pathogenesis of Pregnancy-Induced Hypertension.
abstract: Pregnancy-induced hypertension diseases are classified as gestational hypertension, preeclampsia, or eclampsia. The mechanisms of their development and prediction are still to be discovered. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor secreted by the placenta during the first trimester of human pregnancy that was shown to control trophoblast invasion, to be upregulated by hypoxia, and to be abnormally elevated in pathological pregnancies complicated with preeclampsia and intrauterine growth restriction. These findings suggested that sustaining EG-VEGF levels beyond the first trimester of pregnancy may contribute to pregnancy-induced hypertension. To test this hypothesis, osmotic minipumps delivering EG-VEGF were implanted subcutaneously into gravid OF1 (Oncins France 1) mice on day 11.5 post coitus, which is equivalent to the end of the first trimester of human pregnancy. Mice were euthanized at 15.5 and 18.5 days post coitus to assess (1) litter size, placental, and fetal weights; (2) placental histology and function; (3) maternal blood pressure; (4) renal histology and function; and (5) circulating soluble fms-like tyrosine kinase 1 and soluble endoglin. Increased EG-VEGF levels caused significant defects in placental organization and function. Both increased hypoxia and decreased trophoblast invasion were observed. Treated mice had elevated circulating soluble fms-like tyrosine kinase 1 and soluble endoglin and developed gestational hypertension with dysregulated maternal kidney function. EG-VEGF effect on the kidney function was secondary to its effects on the placenta as similarly treated male mice had normal kidney functions. Altogether, these data provide a strong evidence to confirm that sustained EG-VEGF beyond the first trimester of pregnancy contributes to the development of pregnancy-induced hypertension.
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Frédéric
authors.initials: F
authors.lastname: Sergent
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Pascale
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouillet
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Vanessa
authors.initials: V
authors.lastname: Garnier
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Aude
authors.initials: A
authors.lastname: Salomon
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Padma
authors.initials: P
authors.lastname: Murthi
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benharouga
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale, Grenoble, France (F.S., P.H., S.B., V.G., A.S., J.-J.F., N.A.); University Grenoble-Alpes, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Commissariat à l'Energie Atomique (CEA), BIG (Biosciences Biotechnology Institute of Grenoble)-Biology of Cancer and Infection, Grenoble, France (F.S., P.H., S.B., V.G., A.S., M.B., J.-J.F., N.A.); Department of Obstetrics and Gynaecology, University Hospital of Grenoble, La Tronche, France (P.H.); Laboratoire d'Aide à la Procréation-CECOS, University Hospital of Grenoble, La Tronche, France (S.B.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France (M.B.); and Department of Medicine, School of Clinical Sciences, Monash university and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia (P.M.).
authors.forename: Nadia
authors.initials: N
authors.lastname: Alfaidy
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D046110:Hypertension, Pregnancy-Induced / Q000235:genetics / Q000503:physiopathology*; D007150:Immunohistochemistry; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D010920:Placenta / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011270:Pregnancy, Animal; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012680:Sensitivity and Specificity; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000097:blood* / Q000494:pharmacology
chemical_list: C525015:PKR1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
keywords: endocrine gland-derived endothelial growth factor; hypertension; preeclampsia; pregnancy-induced hypertension; prokineticin 1