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Nat Commun. 2019 Jun 6;10(1):2477. doi: 10.1038/s41467-019-10219-8.

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

Author information

1
Neurosciences Graduate Program, University of California, San Diego, La Jolla, CA, 92037, USA.
2
Medical Scientist Training Program, University of California, San Diego, La Jolla, CA, 92037, USA.
3
Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, 94303, USA.
4
Department of Pharmacology, University of California, San Diego, La Jolla, CA, 92037, USA.
5
Shiley Eye Institute, Department of Ophthalmology, University of California, San Diego, La Jolla, CA, 92037, USA.
6
Department of Pharmacology, University of California, San Diego, La Jolla, CA, 92037, USA. rdaneman@ucsd.edu.

Abstract

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.

PMID:
31171770
DOI:
10.1038/s41467-019-10219-8

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