Placental Growth Factor Is Secreted by the Human Endometrium and Has Potential Important Functions during Embryo Development and Implantation.

Natalie K Binder,Lois A Salamonsen,Natalie J Hannan,Tu’Uhevaha J Kaitu’U-Lino,David K Gardner,Jemma Evans,Xiaoqin Ye

doi:10.1371/journal.pone.0163096

Abstract

Embryo implantation requires synchronized dialogue between the receptive endometrium and activated blastocyst via locally produced soluble mediators. During the mid-secretory (MS) phase of the menstrual cycle, increased glandular secretion into the uterine lumen provides important mediators that modulate the endometrium and support the conceptus during implantation. Previously we demonstrated the importance of vascular endothelial growth factor (VEGF) in the human uterus, particularly with respect to embryo implantation. In the current study, proteomic analysis of human uterine lavage fluid identified the presence of placental growth factor (PlGF) a homolog of VEGF, that binds the VEGF receptor 1 (VEGFR1). Analysis of immunostaining for PlGF in human endometrial tissue across the menstrual cycle (from both fertile and infertile women) revealed PlGF was predominantly localised to glandular and luminal epithelial cells, with staining in the decidualising stromal cells surrounding the maternal spiral arteries in the secretory phase of the menstrual cycle. Immunoreactive PlGF was also detected in subpopulations of endometrial leukocytes. Functional studies demonstrated that culturing mouse embryos with recombinant human (rh)PlGF enhanced blastocyst cell number and outgrowth. Furthermore, treatment of human endometrial epithelial cells (EEC) with rhPlGF enhanced EEC adhesion. Taken together, these data demonstrate that PlGF is abundant in the human endometrium, and secreted into the uterine lumen where it mediates functional changes in cellular adhesion with important roles in implantation.

Highlights

The human endometrium is receptive to blastocyst implantation for only ~4 days in the midsecretory (MS) phase of each menstrual cycle [1]
Placental growth factor was identified in human uterine fluid using proteomic analysis (LC-MS/MS) of uterine lavage from the mid-secretory phase of women with proven fertility
Positive immunostaining was detected in the human endometrium from all stages of the menstrual cycle, predominantly localized to the glandular and luminal epithelium, with additional immunostaining in decidualised stromal cells, where present, and leukocytes

Summary

Introduction

The human endometrium is receptive to blastocyst implantation for only ~4 days in the midsecretory (MS) phase of each menstrual cycle [1]. Our previous work demonstrated women with unexplained infertility were shown to have reduced levels of vascular endothelial growth factor A (VEGFA) in uterine fluid[11] and a non-vascular role of endometrial derived VEGFA with functional actions on both the maternal surface epithelium and on the peri-implantation blastocyst [11, 14]. The current study determined that placental growth factor (PlGF) a VEGF homolog, is present in human uterine fluid. In this study the localisation of PlGF in human endometrium across the menstrual cycle and potential roles of PlGF on the peri-implantation embryo and the endometrial epithelium are demonstrated. PlGF has substantial effects on both endometrial epithelial adhesive capacity and on blastocyst outgrowth

Ethical approval

Results

Discussion