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NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy
Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada;McGill Univ, Dept Neurol Neurosurg, Montreal, PQ H3A 2B4, Canada.
Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada.
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 10, p. 4538-4547Article in journal (Refereed) Published
Abstract [en]

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 beta-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.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2019. Vol. 116, no 10, p. 4538-4547
Keywords [en]
diabetic macular edema, diabetic retinopathy, NOTCH, JAG1, DLL4
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-379896DOI: 10.1073/pnas.1814711116ISI: 000460242100088PubMedID: 30787185OAI: oai:DiVA.org:uu-379896DiVA, id: diva2:1298590
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-25Bibliographically approved

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