title: An EG-VEGF-Dependent Decrease in Homeobox GeneNKX3.1Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction.
abstract: Idiopathic fetal growth restriction (FGR) is frequently associated with placental insufficiency. Previous reports have provided evidence that endocrine gland-derived vascular endothelial growth factor (EG-VEGF), a placental secreted protein, is expressed during the first trimester of pregnancy, controls both trophoblast proliferation and invasion, and its increased expression is associated with human FGR. In this study, we hypothesize that EG-VEGF-dependent changes in placental homeobox gene expressions contribute to trophoblast dysfunction in idiopathic FGR. The changes in EG-VEGF-dependent homeobox gene expressions were determined using a homeobox gene cDNA array on placental explants of 8-12 wks gestation after stimulation with EG-VEGFin vitrofor 24 h. The homeobox gene array identified a greater-than-five-fold increase inHOXA9,HOXC8,HOXC10,HOXD1,HOXD8,HOXD9andHOXD11, whileNKX 3.1showed a greater-than-two-fold decrease in mRNA expression compared with untreated controls. Homeobox geneNKX3.1was selected as a candidate because it is a downstream target of EG-VEGF and its expression and functional roles are largely unknown in control and idiopathic FGR-affected placentae. Real-time PCR and immunoblotting showed a significant decrease inNKX3.1mRNA and protein levels, respectively, in placentae from FGR compared with control pregnancies. Gene inactivationin vitrousing short-interference RNA specific forNKX3.1demonstrated an increase in BeWo cell differentiation and a decrease in HTR-8/SVneo proliferation. We conclude that the decreased expression of homeobox geneNKX3.1downstream of EG-VEGF may contribute to the trophoblast dysfunction associated with idiopathic FGR pregnancies.
authors.affiliation: Department of Perinatal Medicine Pregnancy Research Centre, The Royal Women's Hospital and The University of Melbourne Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Victoria, Australia.|Department of Medicine, Monash University, Victoria, Australia.
authors.forename: Padma
authors.initials: P
authors.lastname: Murthi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France.|Université Grenoble-Alpes, 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, La Tronche, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouillet
authors.affiliation: Department of Perinatal Medicine Pregnancy Research Centre, The Royal Women's Hospital and The University of Melbourne Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Victoria, Australia.
authors.forename: Anita
authors.initials: A
authors.lastname: Pratt
authors.affiliation: Department of Perinatal Medicine Pregnancy Research Centre, The Royal Women's Hospital and The University of Melbourne Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Victoria, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Borg
authors.affiliation: Department of Perinatal Medicine Pregnancy Research Centre, The Royal Women's Hospital and The University of Melbourne Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Victoria, Australia.
authors.forename: Bill
authors.initials: B
authors.lastname: Kalionis
authors.affiliation: Laboratory of Tumor and Developmental Biology, University of Liège, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Goffin
authors.affiliation: Department of Obstetrics and Gynecology, Hôpital Cochin, Maternité Port-Royal, Université Rene Descartes, Paris, France.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Tsatsaris
authors.affiliation: Laboratory of Tumor and Developmental Biology, University of Liège, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Munaut
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France.|Université Grenoble-Alpes, Grenoble, France.|Commissariat à L'Energie Atomique (CEA), iRTSV-Biology of Cancer and Infection, Grenoble, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benharouga
authors.affiliation: INSERM, U1139; Universite Paris Descartes, UMR-S1139; and PremUp Foundation, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fournier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France.|Université Grenoble-Alpes, Grenoble, France.|Commissariat à L'Energie Atomique (CEA), iRTSV-Biology of Cancer and Infection, Grenoble, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Alfaidy