COUP-TFI deletion affects angiogenesis and apoptosis related gene expression in mouse placenta: results of an explorative study

Abstract

COUP-TFI deletion affects angiogenesis and apoptosis related gene expression in mouse placenta: results of an explorative study Luigi Viola1 , Stefania Marzinotto2 , Michele Bertacchi3 , Ambrogio P Londero4,5,*, Maria Orsaria6 , Serena Bertozzi5,7 , Lorenza Driul4 , Carla Di Loreto8 , Michèle Studer3 , Laura Mariuzzi8 , Arrigo Fruscalzo9,* 1Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy 2Department of Laboratory Medicine, ASUFC, 33100 Udine, Italy 3Université Côte d’Azur (UCA), CNRS, Inserm, iBV, 06108 Nice, France 4Obstetrics and Gynecology, AOU S.M. della Misericordia, University of Udine, 33100 Udine, Italy 5Ennergi Research (non-profit organization), via Talmassons1, 33050 Lestizza (UD), Italy 6 Institute of Surgical Pathology, Department of Laboratory Medicine, ASUFC, 33100 Udine, Italy 7Clinic of Surgery, AOU Santa Maria della Misericordia, University of Udine, 33100 Udine, Italy 8 Institute of Surgical Pathology, Department of Medicine – DAME, University of Udine, 33100 Udine, Italy 9Clinic of Obstetrics and Gynecology, University Hospital of Fribourg, 1752 Villars sur Glane, Fribourg, Switzerland *Correspondence: arrigo.fruscalzo@h-fr.ch (Arrigo Fruscalzo); ambrogio.londero@gmail.com (Ambrogio P Londero) Academic Editor: Mahmoud S. Ahmed Submitted: 26 July 2021 Revised: 26 August 2021 Accepted: 13 September 2021 Published: 10 January 2022 Abstract Background: Chicken Ovalbumin Upstream Promoter-Transcription Factor I (COUP-TFI) is a member of the steroid/thyroid nuclear receptor superfamily. The aim of this study was to investigate whether absence of this gene affects placental development and fetal growth in a COUP-TFI knockout mouse model. Methods: Placentas of COUP-TFI-knockout (COUP-TFI KO) and wild-type (WT) were collected at 18.5 days post-coitum. The expression level of the following genes known to be involved in different key molecular pathways was evaluated: BCL2 Associated X (Bax) and B-cell lymphoma 2 (Bcl-2) (apoptosis), p21, p53 and α subunit of inhibin (INHA) (proliferation and apoptosis), vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), hypoxia-inducible factor 1-alpha (HIF1α), Fms related receptor tyrosine kinase 1 (Flt-1), and endoglin (ENG) (angiogenesis). Mouse litter weight at birth was also assessed. Results: RT-qPCR analysis showed increased mRNA expression of VEGF-A and Bax in placental tissue of COUP-TFI KO mice compared to WT mice. We also found a loss in the positive correlation between Bcl-2 and INHA, p21 and ENG, as well as HIF1α and Flt-1 mRNA expression in COUP-TFI mutants. Finally, KO mice were lighter than WT littermates (respectively, the mean weight of COUP-TFI KO mice was 1.3 grams, ± 0.13, compared to 1.6 g, ± 0.14 of WT mice, p < 0.05). Conclusions: Our results show that COUP-TFI deletion is associated with a lower birth weight in mice and increased placental transcript expression of pro-apoptotic Bax and pro-angiogenetic VEGF-A genes. Keywords: COUP Transcription Factor I; Nr2f1/NR2F1; Mouse; Placenta; Angiogenesis; Apoptosis