NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy

Proceedings of the National Academy of Sciences of the United States of America
Khalil MiloudiPrzemyslaw Sapieha

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.

References

Aug 1, 1992·Neuropharmacology·G CalapaiA P Caputi
Jan 1, 1997·Annual Review of Cell and Developmental Biology·A S YapB M Gumbiner
Jun 17, 1998·Ophthalmology·S E MossB E Klein
Apr 12, 2000·Seminars in Ophthalmology·D A AntonettiT W Gardner
Feb 28, 2001·Proceedings of the National Academy of Sciences of the United States of America·D FukumuraR K Jain
Apr 14, 2004·Archives of Ophthalmology·John H KempenUNKNOWN Eye Diseases Prevalence Research Group
Sep 24, 2005·Nature·Sara M Weis, David A Cheresh
Apr 25, 2006·Nature Reviews. Molecular Cell Biology·Anna-Karin OlssonLena Claesson-Welsh
Aug 9, 2006·The Journal of Cell Biology·Maria Grazia LampugnaniElisabetta Dejana
Feb 14, 2007·Proceedings of the National Academy of Sciences of the United States of America·I B LobovS J Wiegand
Feb 14, 2007·Proceedings of the National Academy of Sciences of the United States of America·Steven SuchtingAnne Eichmann
Jun 9, 2007·Circulation Research·Jennifer J Hofmann, M Luisa Iruela-Arispe
Dec 22, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Guo-Rui DouHua Han
May 17, 2008·The Journal of Clinical Investigation·Lea ScheppkeMartin Friedlander
Mar 25, 2010·Journal of Cell Science·Maria Grazia LampugnaniElisabetta Dejana
Sep 8, 2010·Current Topics in Developmental Biology·Thomas Gridley
Oct 12, 2010·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Minhua ZhengHua Han
Jan 5, 2011·Diabetes·Hans-Peter HammesMichael Brownlee
Aug 16, 2011·Nature Cell Biology·Chulan KwonDeepak Srivastava
Oct 13, 2011·Molecular Medicine·Guo-Rui DouHua Han
Mar 8, 2012·Current Opinion in Hematology·Elisabetta Dejana, Costanza Giampietro
Mar 9, 2012·Trends in Cell Biology·Peter AndersenChulan Kwon
Jun 13, 2012·The Journal of Experimental Medicine·Zuyue SunLena Claesson-Welsh
Jan 9, 2014·Science Signaling·Carmen M WarrenM Luisa Iruela-Arispe
Jul 13, 2014·Investigative Ophthalmology & Visual Science·Joseph F Arboleda-VelasquezPatricia A D'Amore
Sep 2, 2014·Developmental Cell·Natalie HudsonPatric Turowski

❮ Previous
Next ❯

Citations

Sep 12, 2019·Current Diabetes Reports·Avinash HonasogeRithwick Rajagopal
Oct 13, 2020·Tissue Engineering. Part B, Reviews·Kathleen Zohorsky, Kibret Mequanint
Jan 21, 2021·Nature Reviews. Endocrinology·David A AntonettiAlan W Stitt
Oct 15, 2020·International Journal of Molecular Sciences·Hu Huang
Jan 15, 2021·Journal of Cell Science·Oscar M J A StassenCecilia M Sahlgren
Dec 6, 2020·Cell Death & Disease·Udayan BhattacharyaResham Bhattacharya
May 13, 2021·Experimental Eye Research·Nidhi KumariSenthil Kumar Ganesan
Jun 26, 2021·Pharmacology & Therapeutics·Sorabh Sharma, Craig E Brown
Jul 29, 2021·Advanced Science·Sevgican DemirBilgen Ekim Üstünel
Aug 29, 2021·Neurobiology of Learning and Memory·Carla DalmazPatrícia P Silveira
Aug 11, 2021·The Journal of Infectious Diseases·Dagmar HildebrandThirumalaisamy P Velavan
Dec 12, 2021·Scientific Reports·Birses DebirM Burcin Unlu
Oct 17, 2021·Journal of Cardiovascular Pharmacology·Tianyou WangZhongqun Wang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adherens Junctions

An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques). Adherens junctions uniquely disassemble in uterine epithelial cells to allow the blastocyst to penetrate between epithelial cells. Discover the latest research on adherens junctions here.

Cadherins and Catenins

Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells: alpha-catenin can bind to β-catenin and can also bind actin. β-catenin binds the cytoplasmic domain of some cadherins. Discover the latest research on cadherins and catenins here.