NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy
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 c...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 10; pp. 4538 - 4547 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
05.03.2019
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| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8424 1091-6490 1091-6490 |
| DOI | 10.1073/pnas.1814711116 |
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| 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. |
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| AbstractList | 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. 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.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. Diabetic retinopathy is a major cause of blindness in the working population. The most common cause of visual impairment in diabetic patients is diabetic macular edema (DME). Roughly 40% of patients with DME respond poorly to anti-VEGF therapies, which are a standard of care. Here we provide mechanistic insight for the critical role of NOTCH1 signaling in compromising endothelial junction integrity during diabetes. Besides activating canonical transcriptional pathways, we find that NOTCH1 signaling also provokes disruption of endothelial junctions via noncanonical mechanisms, such as production of nitric oxide and activation of Src signaling, leading to vascular endothelial-cadherin and β-catenin dissociation. Our findings have implications for future therapeutic interventions given that we find elevated NOTCH1 ligands in the vitreous of patients with DME and that their neutralization decreases pathologic vascular permeability. 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. 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. |
| Author | Delisle, Chantal Binet, Francois Joyal, Jean-Sebastien Gratton, Jean-Philippe Miloudi, Khalil Oubaha, Malika Buscarlet, Manuel Mawambo, Gaëlle Cerani, Agustin Crespo-Garcia, Sergio Bentley, Katie Rezende, Flavio Tétreault, Nicolas Wilson, Ariel M. Chidiac, Rony Mallette, Frédérick A. Larrivée, Bruno Sapieha, Przemyslaw Ménard, Catherine Guber, Vera Dejda, Agnieszka Cagnone, Gael |
| Author_xml | – sequence: 1 givenname: Khalil surname: Miloudi fullname: Miloudi, Khalil – sequence: 2 givenname: Malika surname: Oubaha fullname: Oubaha, Malika – sequence: 3 givenname: Catherine surname: Ménard fullname: Ménard, Catherine – sequence: 4 givenname: Agnieszka surname: Dejda fullname: Dejda, Agnieszka – sequence: 5 givenname: Vera surname: Guber fullname: Guber, Vera – sequence: 6 givenname: Gael surname: Cagnone fullname: Cagnone, Gael – sequence: 7 givenname: Ariel M. surname: Wilson fullname: Wilson, Ariel M. – sequence: 8 givenname: Nicolas surname: Tétreault fullname: Tétreault, Nicolas – sequence: 9 givenname: Gaëlle surname: Mawambo fullname: Mawambo, Gaëlle – sequence: 10 givenname: Francois surname: Binet fullname: Binet, Francois – sequence: 11 givenname: Rony surname: Chidiac fullname: Chidiac, Rony – sequence: 12 givenname: Chantal surname: Delisle fullname: Delisle, Chantal – sequence: 13 givenname: Manuel surname: Buscarlet fullname: Buscarlet, Manuel – sequence: 14 givenname: Agustin surname: Cerani fullname: Cerani, Agustin – sequence: 15 givenname: Sergio surname: Crespo-Garcia fullname: Crespo-Garcia, Sergio – sequence: 16 givenname: Katie surname: Bentley fullname: Bentley, Katie – sequence: 17 givenname: Flavio surname: Rezende fullname: Rezende, Flavio – sequence: 18 givenname: Jean-Sebastien surname: Joyal fullname: Joyal, Jean-Sebastien – sequence: 19 givenname: Frédérick A. surname: Mallette fullname: Mallette, Frédérick A. – sequence: 20 givenname: Jean-Philippe surname: Gratton fullname: Gratton, Jean-Philippe – sequence: 21 givenname: Bruno surname: Larrivée fullname: Larrivée, Bruno – sequence: 22 givenname: Przemyslaw surname: Sapieha fullname: Sapieha, Przemyslaw |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30787185$$D View this record in MEDLINE/PubMed https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-379896$$DView record from Swedish Publication Index |
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| Keywords | DLL4 NOTCH JAG1 diabetic retinopathy diabetic macular edema |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Edited by Janet R. Sparrow, Columbia University, New York, NY, and accepted by Editorial Board Member Carl F. Nathan January 18, 2019 (received for review August 28, 2018) 1K.M., M.O., and C.M. contributed equally to this work. Author contributions: K.M., M.O., B.L., and P.S. designed research; K.M., M.O., C.M., A.D., V.G., A.M.W., N.T., G.M., F.B., C.D., A.C., S.C.-G., and F.R. performed research; J.-S.J., F.A.M., J.-P.G., B.L., and P.S. contributed new reagents/analytic tools; K.M., M.O., C.M., A.D., G.C., N.T., F.B., R.C., C.D., M.B., A.C., K.B., B.L., and P.S. analyzed data; and K.M., M.O., C.M., B.L., and P.S. wrote the paper. |
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| Snippet | Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial... Diabetic retinopathy is a major cause of blindness in the working population. The most common cause of visual impairment in diabetic patients is diabetic... |
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| SubjectTerms | 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 |
| Title | NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy |
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