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

Nat Commun. 2019 Jun 6;10(1):2477. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amacrine Cells / physiology*
  • Animals
  • Blood-Retinal Barrier / drug effects
  • Blood-Retinal Barrier / growth & development*
  • Blood-Retinal Barrier / innervation
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cholinergic Neurons / drug effects
  • Cholinergic Neurons / physiology*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology*
  • Eye Proteins / metabolism
  • Mice
  • Neovascularization, Physiologic / physiology*
  • Nerve Tissue Proteins / metabolism
  • Nicotinic Agonists / pharmacology
  • Oxygen / adverse effects
  • Pyridines / pharmacology
  • Retinal Diseases
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / physiology*
  • Retinal Neovascularization / etiology
  • Tetrodotoxin / pharmacology
  • Vascular Endothelial Growth Factor A / metabolism
  • beta Catenin / metabolism


  • Bridged Bicyclo Compounds, Heterocyclic
  • CTNNB1 protein, mouse
  • Eye Proteins
  • Ndph protein, mouse
  • Nerve Tissue Proteins
  • Nicotinic Agonists
  • Pyridines
  • Vascular Endothelial Growth Factor A
  • beta Catenin
  • vascular endothelial growth factor A, mouse
  • Tetrodotoxin
  • epibatidine
  • Oxygen