NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 10; pp. 4538 - 4547
• Main Authors: Miloudi, Khalil, Oubaha, Malika, Ménard, Catherine, Dejda, Agnieszka, Guber, Vera, Cagnone, Gael, Wilson, Ariel M., Tétreault, Nicolas, Mawambo, Gaëlle, Binet, Francois, Chidiac, Rony, Delisle, Chantal, Buscarlet, Manuel, Cerani, Agustin, Crespo-Garcia, Sergio, Bentley, Katie, Rezende, Flavio, Joyal, Jean-Sebastien, Mallette, Frédérick A., Gratton, Jean-Philippe, Larrivée, Bruno, Sapieha, Przemyslaw
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.03.2019
• Series: PNAS Plus
• Subjects: Adaptor Proteins, Signal Transducing - biosynthesis; Adherens junctions; Animals; Antigens, CD - metabolism; Biological Sciences; Cadherins; Cadherins - metabolism; Calcium-Binding Proteins - biosynthesis; Capillary Permeability; Diabetes; Diabetes mellitus; diabetic macular edema; Diabetic retinopathy; Diabetic Retinopathy - pathology; DLL4; Edema; Endothelial cells; Enzyme Activation; Hyperglycemia; Hyperglycemia - metabolism; JAG1; Jagged-1 Protein - biosynthesis; Jagged1 protein; Ligands; Mice; Neuronal-glial interactions; Neutralization; Nitric Oxide - biosynthesis; NOTCH; Notch1 protein; Permeability; PNAS Plus; Receptor, Notch1 - metabolism; Retina; Retinal Vessels - metabolism; Retinopathy; Signal Transduction; Signaling; src-Family Kinases - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; β-Catenin; DLL4; NOTCH; JAG1; diabetic retinopathy; diabetic macular edema
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1814711116

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.