Restoring endothelial function by targeting desert hedgehog downstream of klf2 improves critical limb ischemia in adults

Caroline Caradu, Thierry Couffnhal, Candice Chapouly, Sarah Guimbal, Pierre Louis Hollier, Eric Ducasse, Alessandra Bura-Rivière, Mathilde Dubois, Alain Pierre Gadeau, Marie Ange Renault

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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 in?ammatory cytokines. Consequently, we show that Dhh knockdown in ECs promotes endothelial permeability and EC activation and that Dhh agonist prevents TNF-a (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 in?ammation, is associated to major EC dysfunction. By recreating a complex model of critical limb ischemia in diabetic mice, we found that Dhh-signaling agonist signifcantly improved EC function without promoting angiogenesis, which subsequently improved muscle perfusion. Conclusion: Restoring EC function leads to signifcant critical limb ischemia recovery. Dhh appears to be a promising target, downstream of Klf2, to prevent the endothelial dysfunction involved in ischemic vascular diseases.

Original languageEnglish
Pages (from-to)1053-1065
Number of pages13
JournalCirculation Research
Issue number9
StatePublished - 2018
Externally publishedYes


  • Endothelial cells
  • Hedgehogs
  • Inflammation
  • Peripheral arterial disease
  • Therapeutics


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