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

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 and functional validation, we show that deep plexus angiogenesis and paracellular BRB maturation are delayed in Vglut1 -/- retinas where neurons fail to release glutamate. In 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 rescued 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.

Citation

Saptarshi Biswas, Sanjid Shahriar, Galina Bachay, Panos Arvanitis, Danny Jamoul, William J Brunken, Dritan Agalliu. Glutamatergic neuronal activity regulates angiogenesis and blood-retinal barrier maturation via Norrin/β-catenin signaling. bioRxiv : the preprint server for biology. 2024 Jan 15

PMID: 37503079

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