title: G-protein-coupled receptor 91 and succinate are key contributors in neonatal postcerebral hypoxia-ischemia recovery.
abstract: 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.
  
  
  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 growth factor expression was abrogated by a cyclooxygenase inhibitor and a selective prostaglandin E receptor 4 antagonist. This antagonist also abolished succinate-induced neovascularization.
  
  
  CONCLUSIONS
  We uncover a dominant metabolic sensor responsible for post-HI neurovascular adaptation, notably succinate/GPR91, acting via prostaglandin E2-prostaglandin E receptor 4 to govern expression of major angiogenic factors. We propose that pharmacological intervention targeting GPR91 could improve post-HI brain recovery.
authors.affiliation: From the Department of Pediatrics, Research Center-CHU Ste-Justine, Montréal, Quebec, Canada (D.H., O.R., J.C.H., T.Z., X.H., J.-C.L., G.A.M., S.C.); Departments of Pharmacology (D.H., F.D., S.C.) and Biomedical Sciences (O.R., M.N.-V.), Université de Montréal, Montréal, Quebec, Canada; and Department of Pharmacology and Therapeutics (M.S., B.N., S.C.), Goodman Cancer Research and Metabolomics Core Facility (O.A.M.), McGill University, Montréal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hamel
authors.forename: Melanie
authors.initials: M
authors.lastname: Sanchez
authors.forename: François
authors.initials: F
authors.lastname: Duhamel
authors.forename: Olivier
authors.initials: O
authors.lastname: Roy
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Honoré
authors.forename: Baraa
authors.initials: B
authors.lastname: Noueihed
authors.forename: Tianwei
authors.initials: T
authors.lastname: Zhou
authors.forename: Mathieu
authors.initials: M
authors.lastname: Nadeau-Vallée
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lavoie
authors.forename: Grant
authors.initials: G
authors.lastname: Mitchell
authors.forename: Orval A
authors.initials: OA
authors.lastname: Mamer
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002540:Cerebral Cortex / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019802:Succinic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D042501:Angiogenic Proteins; D016861:Cyclooxygenase Inhibitors; C531499:GPR91 protein, mouse; D018696:Neuroprotective Agents; D011448:Prostaglandin Antagonists; C545652:Ptger4 protein, rat; D043562:Receptors, G-Protein-Coupled; D058309:Receptors, Prostaglandin E, EP4 Subtype; D019802:Succinic Acid; D015232:Dinoprostone
keywords: GPR91 protein, mouse; animals, newborn; hypoxia-ischemia, brain; intracellular signaling peptides and proteins; succinic acid