NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy

Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4538-4547. doi: 10.1073/pnas.1814711116. Epub 2019 Feb 20.

Abstract

Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from β-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.

Keywords: DLL4; JAG1; NOTCH; diabetic macular edema; diabetic retinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Animals
  • Antigens, CD / metabolism
  • Cadherins / metabolism
  • Calcium-Binding Proteins / biosynthesis
  • Capillary Permeability*
  • Diabetic Retinopathy / pathology*
  • Enzyme Activation
  • Hyperglycemia / metabolism
  • Jagged-1 Protein / biosynthesis
  • Mice
  • Nitric Oxide / biosynthesis
  • Receptor, Notch1 / metabolism*
  • Retinal Vessels / metabolism
  • Signal Transduction*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • src-Family Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Cadherins
  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Notch1 protein, mouse
  • Receptor, Notch1
  • cadherin 5
  • Nitric Oxide
  • Vascular Endothelial Growth Factor Receptor-2
  • src-Family Kinases

Grant support