Cholinergic neural activity directs retinal layer-specific angiogenesis and blood retinal barrier formation

• Published in: Nature communications Vol. 10; no. 1; pp. 2477 - 10
• Main Authors: Weiner, G. A., Shah, S. H., Angelopoulos, C. M., Bartakova, A. B., Pulido, R. S., Murphy, A., Nudleman, E., Daneman, R., Goldberg, J. L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.06.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 14/63; 38; 631/136; 631/378; 631/378/1341; 631/80; 64/60; 96; Amacrine Cells - physiology; Angiogenesis; Animals; beta Catenin - metabolism; Blood vessels; Blood-Retinal Barrier - drug effects; Blood-Retinal Barrier - growth & development; Blood-Retinal Barrier - innervation; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Central nervous system; Cholinergic Neurons - drug effects; Cholinergic Neurons - physiology; Cholinergics; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - physiology; Eye Proteins - metabolism; Growth factors; Humanities and Social Sciences; Mice; multidisciplinary; Neovascularization, Physiologic - physiology; Nerve Tissue Proteins - metabolism; Neural networks; Nicotinic Agonists - pharmacology; Oxygen - adverse effects; Pyridines - pharmacology; Regional development; Retina; Retinal Diseases; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - physiology; Retinal Neovascularization - etiology; Retinopathy; Science; Science (multidisciplinary); Tetrodotoxin - pharmacology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Wnt protein; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10219-8

Blood vessels in the central nervous system (CNS) develop unique features, but the contribution of CNS neurons to regulating those features is not fully understood. We report that inhibiting spontaneous cholinergic activity or reducing starburst amacrine cell numbers prevents invasion of endothelial cells into the deep layers of the retina and causes blood-retinal-barrier (BRB) dysfunction in mice. Vascular endothelial growth factor (VEGF), which drives angiogenesis, and Norrin, a Wnt ligand that induces BRB properties, are decreased after activity blockade. Exogenous VEGF restores vessel growth but not BRB function, whereas stabilizing beta-catenin in endothelial cells rescues BRB dysfunction but not vessel formation. We further identify that inhibiting cholinergic activity reduces angiogenesis during oxygen-induced retinopathy. Our findings demonstrate that neural activity lies upstream of VEGF and Norrin, coordinating angiogenesis and BRB formation. Neural activity originating from specific neural circuits may be a general mechanism for driving regional angiogenesis and barrier formation across CNS development. During retinal development, waves of cholinergic neural activity play a role in retinal circuit development. Here, the authors show that this activity also contributes to layer-specific angiogenesis and formation of the blood-retinal barrier.