Nuclear localization of platelet-activating factor receptor controls retinal neovascularization

作者：Vikrant K. Bhosle, José Carlos Rivera, Tianwei Zhou, Samy Omri, Mélanie Sanchez, David Hamel, Tang Zhu, Raphaël Rouget, Areej Al Rabea, Xin Hou, Isabelle Lahaie, Alfredo Ribeiro‐da‐Silva, Sylvain Chemtob · 发表于：Cell Discovery · 年份：2016 · DOI：10.1038/celldisc.2016.17 · 被引用次数：47 · 研究领域：Retinal Development and Disorders、Blood Coagulation and Thrombosis Mechanisms、Cell Adhesion Molecules Research

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.