Neuronal ER stress impedes myeloid-cell-induced vascular regeneration through IRE1α degradation of netrin-1.

Cell metabolism (2013-03-12)
François Binet, Gaëlle Mawambo, Nicholas Sitaras, Nicolas Tetreault, Eric Lapalme, Sandra Favret, Agustin Cerani, Dominique Leboeuf, Sophie Tremblay, Flavio Rezende, Aimee M Juan, Andreas Stahl, Jean-Sebastien Joyal, Eric Milot, Randal J Kaufman, Martin Guimond, Timothy E Kennedy, Przemyslaw Sapieha

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.

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DAPI, for nucleic acid staining
4′,6-Diamidino-2-phenylindole dihydrochloride, powder, BioReagent, suitable for cell culture, ≥98% (HPLC and TLC), suitable for fluorescence
4′,6-Diamidino-2-phenylindole dihydrochloride, BioReagent, suitable for fluorescence, ≥95.0% (HPLC)