KLF2
缺血
医学
下游(制造业)
沙漠(哲学)
刺猬
功能(生物学)
下调和上调
内科学
细胞生物学
生物
信号转导
工程类
认识论
基因
哲学
生物化学
运营管理
作者
Caroline Caradu,Thierry Couffinhal,Candice Chapouly,Sarah Guimbal,Pierre-Louis Hollier,Éric Ducasse,A. Bura-Rivière,Mathilde Dubois,Alain‐Pierre Gadeau,Marie-Ange Renault
出处
期刊:Circulation Research
[Ovid Technologies (Wolters Kluwer)]
日期:2018-10-12
卷期号:123 (9): 1053-1065
被引量:40
标识
DOI:10.1161/circresaha.118.313177
摘要
Klf (kruppel-like factor) 2 is critical to establish and maintain endothelial integrity.Therefore, determining upstream and downstream mediators of Klf2 would lead to alternative therapeutic targets in cardiovascular disease management.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.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.
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