G-Protein–Coupled Receptor 91 and Succinate Are Key Contributors in Neonatal Postcerebral Hypoxia-Ischemia Recovery

作者：David Hamel, Mélanie Sanchez, François Duhamel, Olivier Roy, Jean‐Claude Honoré, Baraa Noueihed, Tianwei Ellen Zhou, Mathieu Nadeau‐Vallée, Xin Hou, Jean-Claude Lavoie, Grant A. Mitchell, Orval Mamer, Sylvain Chemtob · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2013 · DOI：10.1161/atvbaha.113.302131 · 被引用次数：87 · 研究领域：Neonatal and fetal brain pathology、Neonatal Respiratory Health Research、Angiogenesis and VEGF in Cancer

OBJECTIVE: Prompt post-hypoxia-ischemia (HI) revascularization has been suggested to improve outcome in adults and newborn subjects. Other than hypoxia-inducible factor, sensors of metabolic demand remain largely unknown. During HI, anaerobic respiration is arrested resulting in accumulation of carbohydrate metabolic intermediates. As such succinate readily increases, exerting its biological effects via a specific receptor, G-protein-coupled receptor (GPR) 91. We postulate that succinate/GPR91 enhances post-HI vascularization and reduces infarct size in a model of newborn HI brain injury. APPROACH AND RESULTS: The Rice-Vannucci model of neonatal HI was used. Succinate was measured by mass spectrometry, and microvascular density was evaluated by quantification of lectin-stained cryosection. Gene expression was evaluated by real-time polymerase chain reaction. Succinate levels rapidly increased in the penumbral region of brain infarcts. GPR91 was foremost localized not only in neurons but also in astrocytes. Microvascular density increased at 96 hours after injury in wild-type animals; it was diminished in GPR91-null mice leading to an increased infarct size. Stimulation with succinate led to an increase in growth factors implicated in angiogenesis only in wild-type mice. To explain the mode of action of succinate/GPR91, we investigated the role of prostaglandin E2-prostaglandin E receptor 4, previously proposed in neural angiogenesis. Succinate-induced vascular endothelial gro...