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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.
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.
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1 University of California, San Diego, Neurosciences Graduate Program, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California, San Diego, Medical Scientist Training Program, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)
2 University of California, San Diego, Neurosciences Graduate Program, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California, San Diego, Medical Scientist Training Program, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); Stanford University, Spencer Center for Vision Research, Byers Eye Institute, Palo Alto, USA (GRID:grid.168010.e) (ISNI:0000000419368956)
3 University of California, San Diego, Department of Pharmacology, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)
4 University of California, San Diego, Shiley Eye Institute, Department of Ophthalmology, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)
5 Stanford University, Spencer Center for Vision Research, Byers Eye Institute, Palo Alto, USA (GRID:grid.168010.e) (ISNI:0000000419368956); University of California, San Diego, Shiley Eye Institute, Department of Ophthalmology, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)