CARADU, Caroline; COUFFINHAL, Thierry; CHAPOULY, Candice; GUIMBAL, Sarah; HOLLIER, Pierre-Louis; DUCASSE, Eric; BURA-RIVIÈRE, Alessandra; DUBOIS, Mathilde; GADEAU, Alain-Pierre; RENAULT, Marie-Ange

doi:10.1161/CIRCRESAHA.118.313177

Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases

COUFFINHAL, Thierry

Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases

CHAPOULY, Candice
Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases

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Article de revue

Ce document a été publié dans

Circulation Research. 2018, vol. 123, n° 9, p. 1053–1065

Résumé en anglais

RATIONALE: Klf (kruppel-like factor) 2 is critical to establish and maintain endothelial integrity. OBJECTIVE: Therefore, determining upstream and downstream mediators of Klf2 would lead to alternative therapeutic targets in cardiovascular disease management. METHODS AND RESULTS: Here we identify Dhh (desert hedgehog) as a downstream effector of Klf2, whose expression in endothelial cells (ECs) is upregulated by shear stress and decreased by inflammatory cytokines. Consequently, we show that Dhh knockdown in ECs promotes endothelial permeability and EC activation and that Dhh agonist prevents TNF-α (tumor necrosis factor alpha) or glucose-induced EC dysfunction. Moreover, we demonstrate that human critical limb ischemia, a pathological condition linked to diabetes mellitus and inflammation, is associated to major EC dysfunction. By recreating a complex model of critical limb ischemia in diabetic mice, we found that Dhh-signaling agonist significantly improved EC function without promoting angiogenesis, which subsequently improved muscle perfusion. CONCLUSION: Restoring EC function leads to significant critical limb ischemia recovery. Dhh appears to be a promising target, downstream of Klf2, to prevent the endothelial dysfunction involved in ischemic vascular diseases.< Réduire

Mots clés

Article RECHERCHE

Mots clés en anglais

Animal

Animals

Autocrine Communication

Capillary Permeability

Cells

Critical Illness

Cultured

Cyclohexylamines

Cytokines

Disease Models

Endothelial cells

Endothelial Cells

Gene Expression Regulation

Hedgehog Proteins

hedgehogs

Hindlimb

Human Umbilical Vein Endothelial Cells

Humans

Inbred C57BL

inflammation

Inflammation Mediators

Ischemia

Knockout

Kruppel-Like Transcription Factors

Male

Mechanical

Mice

Muscle

Neovascularization

peripheral arterial disease

Physiologic

Regional Blood Flow

Signal Transduction

Skeletal

Stress

therapeutics

Thiophenes

URI

https://oskar-bordeaux.fr/handle/20.500.12278/20882

DOI

http://dx.doi.org/10.1161/CIRCRESAHA.118.313177

Unités de recherche

Biologie des maladies cardiovasculaires (BMC) - UMR 1034

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Restoring Endothelial Function by Targeting Desert Hedgehog Downstream of Klf2 Improves Critical Limb Ischemia in Adults