Homeobox gene TGIF-1 is increased in placental endothelial cells of human fetal growth restriction. Issue 5 (November 2016)

• Record Type: Journal Article
• Authors: Gunatillake, Tilini; Yong, Hannah E J; Dunk, Caroline E; Keogh, Rosemary J; Borg, Anthony J; Cartwright, Judith E; Whitley, Guy S; Murthi, Padma
• Is Part Of: Reproduction. Volume 152:Issue 5(2016)
• Page Start: 457
• Page End: 465
• Publication Date: 2016-11
• Subjects: Reproduction -- Periodicals; Reproduction -- Molecular aspects -- Periodicals; Reproduction -- Immunological aspects -- Periodicals; Reproduction -- Endocrine aspects -- Periodicals; Fertility -- Periodicals; Human reproduction -- Periodicals; 571.805
• DOI: 10.1530/REP-16-0068
• Languages: English
• ISSNs: 1470-1626

Abstract

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.