title: Nuclear localization of platelet-activating factor receptor controls retinal neovascularization.
abstract: Platelet-activating factor (PAF) is a pleiotropic phospholipid with proinflammatory, procoagulant and angiogenic actions on the vasculature. We and others have reported the presence of PAF receptor (Ptafr) at intracellular sites such as the nucleus. However, mechanisms of localization and physiologic functions of intracellular Ptafr remain poorly understood. We hereby identify the importance of C-terminal motif of the receptor and uncover novel roles of Rab11a GTPase and importin-5 in nuclear translocation of Ptafr in primary human retinal microvascular endothelial cells. Nuclear localization of Ptafr is independent of exogenous PAF stimulation as well as intracellular PAF biosynthesis. Moreover, nuclear Ptafr is responsible for the upregulation of unique set of growth factors, including vascular endothelial growth factor, in vitro and ex vivo. We further corroborate the intracrine PAF signaling, resulting in angiogenesis in vivo, using Ptafr antagonists with distinct plasma membrane permeability. Collectively, our findings show that nuclear Ptafr translocates in an agonist-independent manner, and distinctive functions of Ptafr based on its cellular localization point to another dimension needed for pharmacologic selectivity of drugs.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada; CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada; Department of Ophthalmology, Research Centre of Hôpital Maisonneuve-Rosemont, University of Montréal, Montréal, QC, Canada.
authors.forename: Vikrant K
authors.initials: VK
authors.lastname: Bhosle
authors.affiliation: CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada; Department of Ophthalmology, Research Centre of Hôpital Maisonneuve-Rosemont, University of Montréal, Montréal, QC, Canada.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Rivera
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada; CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada; Department of Ophthalmology, Research Centre of Hôpital Maisonneuve-Rosemont, University of Montréal, Montréal, QC, Canada; Department of Medicine, McGill University Health Center, Montreal, QC, Canada.
authors.forename: Tianwei Ellen
authors.initials: TE
authors.lastname: Zhou
authors.affiliation: CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada; Department of Ophthalmology, Research Centre of Hôpital Maisonneuve-Rosemont, University of Montréal, Montréal, QC, Canada.
authors.forename: Samy
authors.initials: S
authors.lastname: Omri
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada; CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada; Department of Ophthalmology, Research Centre of Hôpital Maisonneuve-Rosemont, University of Montréal, Montréal, QC, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Sanchez
authors.affiliation: CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada; Department of Pharmacology, University of Montréal, Montréal, QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hamel
authors.affiliation: CHU Sainte Justine Hospital Research Centre, University of Montréal , Montréal, QC, Canada.
authors.forename: Tang
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada; CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada.
authors.forename: Raphael
authors.initials: R
authors.lastname: Rouget
authors.affiliation: Experimental Surgery, Montreal General Hospital, McGill University , Montréal, QC, Canada.
authors.forename: Areej Al
authors.initials: AA
authors.lastname: Rabea
authors.affiliation: CHU Sainte Justine Hospital Research Centre, University of Montréal , Montréal, QC, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.affiliation: CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada; Department of Ophthalmology, Research Centre of Hôpital Maisonneuve-Rosemont, University of Montréal, Montréal, QC, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lahaie
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada; CHU Sainte Justine Hospital Research Centre, University of Montréal, Montréal, QC, Canada; Department of Ophthalmology, Research Centre of Hôpital Maisonneuve-Rosemont, University of Montréal, Montréal, QC, Canada; Department of Pharmacology, University of Montréal, Montréal, QC, Canada; Departments of Pediatrics and Ophthalmology, Faculty of Medicine, University of Montréal, Montréal, QC, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
keywords: Ptafr; angiogenesis; importin; nuclear GPCR; rab GTPase