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Proc Natl Acad Sci U S A. 2019 Feb 20. pii: 201814711. doi: 10.1073/pnas.1814711116. [Epub ahead of print]

NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy.

Author information

1
Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada.
2
Department of Neurology-Neurosurgery, McGill University, Montreal, QC H3A 2B4 Canada.
3
Department of Biochemistry and Molecular Medicine, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada.
4
Departments of Pediatrics, Ophthalmology, and Pharmacology, Centre Hospitalier Universitaire Ste-Justine Research Center, Montréal, QC H1T 2M4, Canada.
5
Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC H3C 3J7, Canada.
6
Department of Immunology, Genetics and Pathology, Vascular Biology, Uppsala University, 751 85 Uppsala, Sweden.
7
Department of Medicine, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada.
8
Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada; Mike.sapieha@umontreal.ca.

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

PMID:
30787185
DOI:
10.1073/pnas.1814711116

Conflict of interest statement

The authors declare no conflict of interest.

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