title: EG-VEGF controls placental growth and survival in normal and pathological pregnancies: case of fetal growth restriction (FGR).
abstract: Identifiable causes of fetal growth restriction (FGR) account for 30 % of cases, but the remainders are idiopathic and are frequently associated with placental dysfunction. We have shown that the angiogenic factor endocrine gland-derived VEGF (EG-VEGF) and its receptors, prokineticin receptor 1 (PROKR1) and 2, (1) are abundantly expressed in human placenta, (2) are up-regulated by hypoxia, (3) control trophoblast invasion, and that EG-VEGF circulating levels are the highest during the first trimester of pregnancy, the period of important placental growth. These findings suggest that EG-VEGF/PROKR1 and 2 might be involved in normal and FGR placental development. To test this hypothesis, we used placental explants, primary trophoblast cultures, and placental and serum samples collected from FGR and age-matched control women. Our results show that (1) EG-VEGF increases trophoblast proliferation ([(3)H]-thymidine incorporation and Ki67-staining) via the homeobox-gene, HLX (2) the proliferative effect involves PROKR1 but not PROKR2, (3) EG-VEGF does not affect syncytium formation (measurement of syncytin 1 and 2 and β hCG production) (4) EG-VEGF increases the vascularization of the placental villi and insures their survival, (5) EG-VEGF, PROKR1, and PROKR2 mRNA and protein levels are significantly elevated in FGR placentas, and (6) EG-VEGF circulating levels are significantly higher in FGR patients. Altogether, our results identify EG-VEGF as a new placental growth factor acting during the first trimester of pregnancy, established its mechanism of action, and provide evidence for its deregulation in FGR. We propose that EG-VEGF/PROKR1 and 2 increases occur in FGR as a compensatory mechanism to insure proper pregnancy progress.
authors.affiliation: Laboratoire BCI -iRTSV, Institut National de la Santé et de la Recherche Médicale U1036, Biologie du Cancer et de l'Infection, CEA Grenoble, 17, rue des Martyrs, 38054, Grenoble Cedex 9, France.
authors.forename: S
authors.initials: S
authors.lastname: Brouillet
authors.forename: P
authors.initials: P
authors.lastname: Murthi
authors.forename: P
authors.initials: P
authors.lastname: Hoffmann
authors.forename: A
authors.initials: A
authors.lastname: Salomon
authors.forename: F
authors.initials: F
authors.lastname: Sergent
authors.forename: P
authors.initials: P
authors.lastname: De Mazancourt
authors.forename: M
authors.initials: M
authors.lastname: Dakouane-Giudicelli
authors.forename: M N
authors.initials: MN
authors.lastname: Dieudonné
authors.forename: P
authors.initials: P
authors.lastname: Rozenberg
authors.forename: D
authors.initials: D
authors.lastname: Vaiman
authors.forename: S
authors.initials: S
authors.lastname: Barbaux
authors.forename: M
authors.initials: M
authors.lastname: Benharouga
authors.forename: J-J
authors.initials: JJ
authors.lastname: Feige
authors.forename: N
authors.initials: N
authors.lastname: Alfaidy
mesh_terms: D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism* / Q000473:pathology; D015726:Giant Cells / Q000166:cytology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D010929:Placentation; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics / Q000378:metabolism*
chemical_list: C084058:HLX protein, human; D018398:Homeodomain Proteins; C470837:PROKR1 protein, human; C470838:PROKR2 protein, human; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D011994:Recombinant Proteins; D014157:Transcription Factors; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived