Glutamatergic neuronal activity regulates angiogenesis and blood-retinal barrier maturation via Norrin/β-catenin signaling.

Publisher: Cell Press Country of Publication: United States NLM ID: 8809320 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4199 (Electronic) Linking ISSN: 08966273 NLM ISO Abbreviation: Neuron Subsets: MEDLINE

Original Publication: [Cambridge, Mass. : Cell Press, c1988-

Blood-Retinal Barrier*/metabolism ; beta Catenin*/metabolism ; Glutamic Acid*/metabolism ; Nerve Tissue Proteins*/metabolism ; Nerve Tissue Proteins*/genetics ; Eye Proteins*/metabolism ; Eye Proteins*/genetics ; Signal Transduction*/physiology; Animals ; Mice ; Vesicular Glutamate Transport Protein 1/metabolism ; Neurons/metabolism ; Mice, Knockout ; Retinal Neovascularization/metabolism ; Retina/metabolism ; Mice, Inbred C57BL ; Angiogenesis

Interactions among neuronal, glial, and vascular components are crucial for retinal angiogenesis and blood-retinal barrier (BRB) maturation. Although synaptic dysfunction precedes vascular abnormalities in many retinal pathologies, how neuronal activity, specifically glutamatergic activity, regulates retinal angiogenesis and BRB maturation remains unclear. Using in vivo genetic studies in mice, single-cell RNA sequencing (scRNA-seq), and functional validation, we show that deep plexus angiogenesis and paracellular BRB maturation are delayed in Vglut1 ^-/- retinas where neurons fail to release glutamate. By contrast, deep plexus angiogenesis and paracellular BRB maturation are accelerated in Gnat1 ^-/- retinas, where constitutively depolarized rods release excessive glutamate. Norrin expression and endothelial Norrin/β-catenin signaling are downregulated in Vglut1 ^-/- retinas and upregulated in Gnat1 ^-/- retinas. Pharmacological activation of endothelial Norrin/β-catenin signaling in Vglut1 ^-/- retinas rescues defects in deep plexus angiogenesis and paracellular BRB maturation. Our findings demonstrate that glutamatergic neuronal activity regulates retinal angiogenesis and BRB maturation by modulating endothelial Norrin/β-catenin signaling.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 Elsevier Inc. All rights reserved.)

Update of: bioRxiv. 2024 Jan 15:2023.07.10.548410. doi: 10.1101/2023.07.10.548410. (PMID: 37503079)

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R01 EY033994 United States EY NEI NIH HHS; R61 HL159949 United States HL NHLBI NIH HHS; R21 NS130265 United States NS NINDS NIH HHS; K99 EY033909 United States EY NEI NIH HHS; R33 HL159949 United States HL NHLBI NIH HHS; R21 EY034696 United States EY NEI NIH HHS; RF1 AG078352 United States AG NIA NIH HHS

Keywords: Müller glia; Norrin/β-catenin signaling; angiogenesis; blood-retinal barrier; glutamate; glutamate transporter 2; neuronal activity; neurovascular development; retina; tight junctions

0 (Ndph protein, mouse)
0 (beta Catenin)
3KX376GY7L (Glutamic Acid)
0 (Nerve Tissue Proteins)
0 (Eye Proteins)
0 (Vesicular Glutamate Transport Protein 1)
0 (CTNNB1 protein, mouse)

Date Created: 20240410 Date Completed: 20240620 Latest Revision: 20240626

20240626

PMC11189759

10.1016/j.neuron.2024.03.011

38599212