title: Homeobox gene TGIF-1 is increased in placental endothelial cells of human fetal growth restriction.
abstract: Aberrant placental angiogenesis is associated with fetal growth restriction (FGR). In mice, targeted disruption of the homeobox gene, transforming growth β-induced factor (Tgif-1), which is also a transcription factor, causes defective placental vascularisation. Nevertheless, the role of TGIF-1 in human placental angiogenesis is unclear. We have previously reported increased TGIF-1 expression in human FGR placentae and demonstrated localisation of TGIF-1 protein in placental endothelial cells (ECs). However, its functional role remains to be investigated. In this study, we aimed to specifically compare TGIF-1 mRNA expression in placental ECs isolated from human FGR-affected pregnancies with gestation-matched control pregnancies in two independent cohorts from Australia and Canada and to identify the functional role of TGIF-1 in placental angiogenesis using the human umbilical vein endothelial cell-derived cell line, SGHEC-7, and primary human umbilical vein ECs. Real-time PCR revealed that TGIF-1 mRNA expression was significantly increased in ECs isolated from FGR-affected placentae compared with that of controls. The functional roles of TGIF-1 were determined in ECs after TGIF-1 siRNA transfection. TGIF-1 inactivation in ECs significantly reduced TGIF-1 at both the mRNA and protein levels, as well as the proliferative and invasive potential, but significantly increased the angiogenic potential. Using angiogenesis PCR screening arrays, we identified ITGAV, NRP-1, ANPGT-1 and ANPGT-2 as novel downstream targets of TGIF-1, after TGIF-1 inactivation in ECs. Collectively, these results show that TGIF-1 regulates EC function and the expression of angiogenic molecules; and when abnormally expressed, may contribute to the aberrant placental angiogenesis observed in FGR.
authors.affiliation: Department of Maternal-Fetal Medicine Pregnancy Research CentreThe Royal Women's Hospital, Parkville, Victoria, Australia Department of Obstetrics and GynaecologyThe University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Tilini
authors.initials: T
authors.lastname: Gunatillake
authors.affiliation: Department of Maternal-Fetal Medicine Pregnancy Research CentreThe Royal Women's Hospital, Parkville, Victoria, Australia Department of Obstetrics and GynaecologyThe University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Hannah E J
authors.initials: HE
authors.lastname: Yong
authors.affiliation: Lunenfeld Tanenbaum-Research InstituteMount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Dunk
authors.affiliation: Department of Maternal-Fetal Medicine Pregnancy Research CentreThe Royal Women's Hospital, Parkville, Victoria, Australia Department of Obstetrics and GynaecologyThe University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Keogh
authors.affiliation: Department of Maternal-Fetal Medicine Pregnancy Research CentreThe Royal Women's Hospital, Parkville, Victoria, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Borg
authors.affiliation: Institute of Cardiovascular and Cell SciencesSt George's, University of London, London, UK.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Cartwright
authors.affiliation: Institute of Cardiovascular and Cell SciencesSt George's, University of London, London, UK.
authors.forename: Guy S
authors.initials: GS
authors.lastname: Whitley
authors.affiliation: Department of Maternal-Fetal Medicine Pregnancy Research CentreThe Royal Women's Hospital, Parkville, Victoria, Australia Department of Obstetrics and GynaecologyThe University of Melbourne, Parkville, Victoria, Australia Department of MedicineSchool of Clinical Sciences, Monash University, Clayton, Victoria, Australia The Ritchie CentreHudson Institute of Medical Research, Clayton, Victoria, Australia padma.murthi@monash.edu.
authors.forename: Padma
authors.initials: P
authors.lastname: Murthi
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D010920:Placenta / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D012097:Repressor Proteins / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology*
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; C097504:TGIF1 protein, human