Abstract

Aberrant placental angiogenesis is associated with fetal growth restriction (FGR). In the mouse, targeted disruption of the homeobox gene, transforming growth β-induced factor (Tgif-1), which is also a transcription factor, causes defective placental vascularisation. Nevertheless, TGIF-1's role 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 following 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, following TGIF-1 inactivation in ECs. Collectively, these results show that increased TGIF-1 in FGR may regulate EC function through mediating the expression of angiogenic molecules and contribute to aberrant placental angiogenesis in FGR pregnancies.