RGD Reference Report - NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy. - Rat Genome Database

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NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy.

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 
Citation: Miloudi K, etal., Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4538-4547. doi: 10.1073/pnas.1814711116. Epub 2019 Feb 20.
RGD ID: 155663348
Pubmed: PMID:30787185   (View Abstract at PubMed)
PMCID: PMC6410871   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1814711116   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
DLL4Humandiabetic retinopathy  ISODll4 (Mus musculus)mRNA,protein:increased expression:retina:RGD 
Dll4Ratdiabetic retinopathy  ISODll4 (Mus musculus)mRNA,protein:increased expression:retina:RGD 
Dll4Mousediabetic retinopathy  IEP mRNA,protein:increased expression:retina:RGD 
HES1Humandiabetic retinopathy  ISOHes1 (Mus musculus)mRNA:increased expression:retina:RGD 
HEY2Humandiabetic retinopathy  ISOHey2 (Mus musculus)mRNA:increased expression:retina:RGD 
Hes1Ratdiabetic retinopathy  ISOHes1 (Mus musculus)mRNA:increased expression:retina:RGD 
Hes1Mousediabetic retinopathy  IEP mRNA:increased expression:retina:RGD 
Hey2Ratdiabetic retinopathy  ISOHey2 (Mus musculus)mRNA:increased expression:retina:RGD 
Hey2Mousediabetic retinopathy  IEP mRNA:increased expression:retina:RGD 
JAG1Humandiabetic retinopathy  ISOJag1 (Mus musculus)mRNA,protein:increased expression:retina:RGD 
Jag1Ratdiabetic retinopathy  ISOJag1 (Mus musculus)mRNA,protein:increased expression:retina:RGD 
Jag1Mousediabetic retinopathy  IEP mRNA,protein:increased expression:retina:RGD 
NOTCH1Humandiabetic retinopathy treatmentISONotch1 (Mus musculus) RGD 
Notch1Ratdiabetic retinopathy treatmentISONotch1 (Mus musculus) RGD 
Notch1Mousediabetic retinopathy treatmentIMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dll4  (delta like canonical Notch ligand 4)
Hes1  (hes family bHLH transcription factor 1)
Hey2  (hes-related family bHLH transcription factor with YRPW motif 2)
Jag1  (jagged canonical Notch ligand 1)
Notch1  (notch receptor 1)

Genes (Mus musculus)
Dll4  (delta like canonical Notch ligand 4)
Hes1  (hes family bHLH transcription factor 1)
Hey2  (hairy/enhancer-of-split related with YRPW motif 2)
Jag1  (jagged 1)
Notch1  (notch 1)

Genes (Homo sapiens)
DLL4  (delta like canonical Notch ligand 4)
HES1  (hes family bHLH transcription factor 1)
HEY2  (hes related family bHLH transcription factor with YRPW motif 2)
JAG1  (jagged canonical Notch ligand 1)
NOTCH1  (notch receptor 1)


Additional Information