title: Neuronal ER stress impedes myeloid-cell-induced vascular regeneration through IRE1α degradation of netrin-1.
abstract: In stroke and proliferative retinopathy, despite hypoxia driven angiogenesis, delayed revascularization of ischemic tissue aggravates the loss of neuronal function. What hinders vascular regrowth in the ischemic central nervous system remains largely unknown. Using the ischemic retina as a model of neurovascular interaction in the CNS, we provide evidence that the failure of reparative angiogenesis is temporally and spatially associated with endoplasmic reticulum (ER) stress. The canonical ER stress pathways of protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme-1α (IRE1α) are activated within hypoxic/ischemic retinal ganglion neurons, initiating a cascade that results in angiostatic signals. Our findings demonstrate that the endoribonuclease IRE1α degrades the classical guidance cue netrin-1. This neuron-derived cue triggers a critical reparative-angiogenic switch in neural macrophage/microglial cells. Degradation of netrin-1, by persistent neuronal ER stress, thereby hinders vascular regeneration. These data identify a neuronal-immune mechanism that directly regulates reparative angiogenesis.
authors.affiliation: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Binet
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Mawambo
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sitaras
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tetreault
authors.forename: Eric
authors.initials: E
authors.lastname: Lapalme
authors.forename: Sandra
authors.initials: S
authors.lastname: Favret
authors.forename: Agustin
authors.initials: A
authors.lastname: Cerani
authors.forename: Dominique
authors.initials: D
authors.lastname: Leboeuf
authors.forename: Sophie
authors.initials: S
authors.lastname: Tremblay
authors.forename: Flavio
authors.initials: F
authors.lastname: Rezende
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Juan
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Joyal
authors.forename: Eric
authors.initials: E
authors.lastname: Milot
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000503:physiopathology*; D004002:Clodronic Acid; D004591:Electrophoresis, Polyacrylamide Gel; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism*; D005434:Flow Cytometry; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007211:Indoles; D016086:Lentivirus; D051379:Mice; D008810:Mice, Inbred C57BL; D042282:Microdissection; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D009474:Neurons / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000503:physiopathology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D004002:Clodronic Acid; D004722:Endoribonucleases; D007211:Indoles; D009414:Nerve Growth Factors; D000075388:Netrin-1; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D019892:eIF-2 Kinase; C000617353:Ntn1 protein, mouse; C007293:DAPI; C510185:Ern1 protein, mouse