Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related/Downregulated by Oncogenes).
| dc.rights.license | embargo | en_US |
| hal.structure.identifier | Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases | |
| dc.contributor.author | CHAPOULY, Candice | |
| hal.structure.identifier | Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases | |
| dc.contributor.author | HOLLIER, Pierre-Louis | |
| hal.structure.identifier | Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases | |
| dc.contributor.author | GUIMBAL, Sarah | |
| hal.structure.identifier | Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases | |
| dc.contributor.author | CORNUAULT, Lauriane | |
| hal.structure.identifier | Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases | |
| dc.contributor.author | GADEAU, Alain-Pierre | |
| hal.structure.identifier | Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases | |
| dc.contributor.author | RENAULT, Marie-Ange | |
| dc.date.accessioned | 2021-03-04T11:16:31Z | |
| dc.date.available | 2021-03-04T11:16:31Z | |
| dc.date.issued | 2020-01-01 | |
| dc.identifier.issn | 1524-4636 | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/26436 | |
| dc.description.abstractEn | Evidences accumulated within the past decades identified hedgehog signaling as a new regulator of endothelium integrity. More specifically, we recently identified Dhh (desert hedgehog) as a downstream effector of Klf2 (Kruppel-like factor 2) in endothelial cells (ECs). The purpose of this study is to investigate whether hedgehog coreceptors Gas1 (growth arrest-specific 1) and Cdon (cell adhesion molecule-related/downregulated by oncogenes) may be used as therapeutic targets to modulate Dhh signaling in ECs. Approach and Results: We demonstrated that both Gas1 and Cdon are expressed in adult ECs and relied on either siRNAs- or EC-specific conditional knockout mice to investigate their role. We found that Gas1 deficiency mainly phenocopies Dhh deficiency especially by inducing VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) overexpression while Cdon deficiency has opposite effects by promoting endothelial junction integrity. At a molecular level, Cdon prevents Dhh binding to Ptch1 (patched-1) and thus acts as a decoy receptor for Dhh, while Gas1 promotes Dhh binding to Smo (smoothened) and as a result potentiates Dhh effects. Since Cdon is upregulated in ECs treated by inflammatory cytokines, including TNF (tumor necrosis factor)-α and Il (interleukin)-1β, we then tested whether Cdon inhibition would promote endothelium integrity in acute inflammatory conditions and found that both fibrinogen and IgG extravasation were decreased in association with an increased Cdh5 (cadherin-5) expression in the brain cortex of EC-specific Cdon knockout mice administered locally with Il-1β. Altogether, these results demonstrate that Gas1 is a positive regulator of Dhh in ECs while Cdon is a negative regulator. Interestingly, Cdon blocking molecules may then be used to promote endothelium integrity, at least in inflammatory conditions. | |
| dc.language.iso | EN | en_US |
| dc.subject.en | Animals | |
| dc.subject.en | Antigens | |
| dc.subject.en | CD | |
| dc.subject.en | Blood-Brain Barrier | |
| dc.subject.en | Cadherins | |
| dc.subject.en | Cell Adhesion Molecules | |
| dc.subject.en | Cell Cycle Proteins | |
| dc.subject.en | Cells | |
| dc.subject.en | Cultured | |
| dc.subject.en | Corneal Neovascularization | |
| dc.subject.en | Disease Models | |
| dc.subject.en | Animal | |
| dc.subject.en | Endothelial Cells | |
| dc.subject.en | Endothelium | |
| dc.subject.en | Corneal | |
| dc.subject.en | Female | |
| dc.subject.en | GPI-Linked Proteins | |
| dc.subject.en | Hedgehog Proteins | |
| dc.subject.en | Humans | |
| dc.subject.en | Inflammation | |
| dc.subject.en | Male | |
| dc.subject.en | Mice | |
| dc.subject.en | 129 Strain | |
| dc.subject.en | Mice | |
| dc.subject.en | Inbred C57BL | |
| dc.subject.en | Mice | |
| dc.subject.en | Knockout | |
| dc.subject.en | Patched-1 Receptor | |
| dc.subject.en | Signal Transduction | |
| dc.subject.en | Smoothened Receptor | |
| dc.title.en | Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related/Downregulated by Oncogenes). | |
| dc.title.alternative | Arterioscler Thromb Vasc Biol | en_US |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.1161/ATVBAHA.120.314441 | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Cardiologie et système cardiovasculaire | en_US |
| dc.identifier.pubmed | 33028094 | en_US |
| bordeaux.journal | Arteriosclerosis, Thrombosis, and Vascular Biology | en_US |
| bordeaux.page | e336-e349 | en_US |
| bordeaux.volume | 40 | en_US |
| bordeaux.hal.laboratories | Biologie des maladies cardiovasculaires - U1034 | en_US |
| bordeaux.issue | 12 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.institution | INSERM | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| bordeaux.import.source | pubmed | |
| hal.export | false | |
| workflow.import.source | pubmed | |
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