Decreased Placental FPR2 in Early Pregnancies That Later Developed Small-For-Gestation Age: A Potential Role of FPR2 in the Regulation of Epithelial-Mesenchymal Transition

Padma Murthi; Gayathri Rajaraman; Jan Jaap H M Erwich; Evdokia Dimitriadis

doi:10.3390/cells9040921

Decreased Placental FPR2 in Early Pregnancies That Later Developed Small-For-Gestation Age: A Potential Role of FPR2 in the Regulation of Epithelial-Mesenchymal Transition

Cells. 2020 Apr 10;9(4):921. doi: 10.3390/cells9040921.

Authors

Padma Murthi^{1

2

3}, Gayathri Rajaraman⁴, Jan Jaap H M Erwich⁵, Evdokia Dimitriadis¹

Affiliations

¹ Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria 3052, Australia.
² Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3168, Australia.
³ Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
⁴ First year college, Victoria University, St Albans, Victoria 3021, Australia.
⁵ Department of Obstetrics and Gynaecology, University of Groningen, 9700 RB Groningen, The Netherlands.

Abstract

We reported earlier that an anti-inflammatory small peptide receptor-formyl peptide receptor-2 (FPR2) was significantly decreased in placentas from third trimester pregnancies complicated with fetal growth restriction (FGR), compared to placentas from uncomplicated control pregnancies, suggesting FPR2 may play a role in the development of FGR. The aim of this study is to investigate whether the actions of FPR2 alters placental growth process in humans. Accordingly, using small-for-gestation age (SGA) as a proxy for FGR, we hypothesize that FPR2 expression is decreased in first-trimester placentas of women who later manifest FGR, and contributes to aberrant trophoblast function and the development of FGR. Chorionic villus sampling (CVS) tissues were collected at 10-12 weeks gestation in 70 patients with singleton fetuses; surplus tissue was used. Real-time PCR and immunoassays were performed to quantitate FPR2 gene and protein expression. Silencing of FPR2 was performed in two independent, trophoblast-derived cell lines, HTR-8/SVneo and JEG-3 to investigate the functional consequences of FPR2 gene downregulation. FPR2 mRNA relative to 18S rRNA was significantly decreased in placentae from SGA-pregnancies (n = 28) compared with controls (n = 52) (p < 0.0001). Placental FPR2 protein was significantly decreased in SGA compared with control (n = 10 in each group, p < 0.05). Proliferative, migratory and invasive potential of the human placental-derived cell lines, HTR-8/SVneo and JEG-3 were significantly reduced in siFPR2 treated cells compared with siCONT control groups. Down-stream signaling molecules, STAT5B and SOCS3 were identified as target genes of FPR2 action in the trophoblast-derived cell lines and in SGA and control chorionic villous tissues. FPR2 is a novel regulator of key molecular pathways and functions in placental development, and its decreased expression in women destined to develop FGR reinforces a placental origin of SGA/FGR, and that it contributes to causing the development of SGA/FGR.

Keywords: epithelial-mesenchymal transition; fetal growth restriction; formyl-peptide receptor-2; placenta; small-for-gestation age.

MeSH terms

Adult
Epithelial-Mesenchymal Transition
Female
Humans
Infant, Newborn
Infant, Small for Gestational Age*
Placenta / metabolism*
Pregnancy
Pregnancy Trimester, First
Receptors, Formyl Peptide / biosynthesis*
Receptors, Formyl Peptide / genetics
Receptors, Formyl Peptide / metabolism
Receptors, Lipoxin / biosynthesis*
Receptors, Lipoxin / genetics
Receptors, Lipoxin / metabolism
Signal Transduction

Substances

FPR2 protein, human
Receptors, Formyl Peptide
Receptors, Lipoxin