Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy.

Deborah Reynaud,Wael Traboulsi,Nadia Alfaidy,Pascale Hoffmann,Gianfranco Balboni,Qun-Yong Zhou,Christel Marquette,Constance Collet,Roland Abi Nahed,Frederic Sergent,Mohamed Benharouga,Padma Murthi

doi:10.3390/biomedicines9030309

Abstract

Endocrine gland derived vascular endothelial growth factor (EG-VEGF) is a canonical member of the prokineticin (PROKs) family. It acts via the two G-protein coupled receptors, namely PROKR1 and PROKR2. We have recently demonstrated that EG-VEGF is highly expressed in the human placenta; contributes to placental vascularization and growth and that its aberrant expression is associated with pregnancy pathologies including preeclampsia and fetal growth restriction. These findings strongly suggested that antagonization of its receptors may constitute a potential therapy for the pregnancy pathologies. Two specific antagonists of PROKR1 (PC7) and for PROKR2 (PKRA) were reported to reverse PROKs adverse effects in other systems. In the view of using these antagonists to treat pregnancy pathologies, a proof of concept study was designed to determine the biological significances of PC7 and PKRA in normal pregnancy outcome. PC7 and PKRA were tested independently or in combination in trophoblast cells and during early gestation in the gravid mouse. Both independent and combined treatments uncovered endogenous functions of EG-VEGF. The independent use of antagonists distinctively identified PROKR1 and PROKR2-mediated EG-VEGF signaling on trophoblast differentiation and invasion; thereby enhancing feto-placental growth and pregnancy outcome. Thus, our study provides evidence for the potential safe use of PC7 or PKRA to improve pregnancy outcome.

Highlights

Introduction conditions of the Creative CommonsProkineticin family includes two conserved small proteins, prokineticin 1 (PROK1) and prokineticin 2 (PROK2) [1,2]
In relation to pregnancy pathologies, we have demonstrated that Endocrine gland derived vascular endothelial growth factor (EG-VEGF) and its receptors are increased in the most threatening pathology of pregnancy, preeclampsia (PE)
We have recently demonstrated that prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2) antagonists reversed EG-VEGF mediated proliferation, migration and invasion of tumor trophoblast cells [6]

Summary

Introduction

Introduction conditions of the Creative CommonsProkineticin family includes two conserved small proteins, prokineticin 1 (PROK1) and prokineticin 2 (PROK2) [1,2]. While VEGF has mainly been reported to play a crucial role in promoting angiogenesis with specific and strong mitogenic and chemotactic actions on endothelial cells and induces microvascular permeability [3], prokineticins act as both pro-angiogenic and proinflammatory factors [1,4,5,6,7]. They bind to two highly related G protein-coupled receptors (GPCRs), prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2) [6,7]. Dysregulation of the prokineticin signaling has been observed in a variety of diseases, such as cancer, ischemia, neurodegeneration, abnormal angiogenesis and pregnancy pathologies [14,23]

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