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.
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 humancritical 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 diabeticmice, 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.
Authors: Brian G Coon; Sushma Timalsina; Matteo Astone; Zhen W Zhuang; Jennifer Fang; Jinah Han; Jurgen Themen; Minhwan Chung; Young Joo Yang-Klingler; Mukesh Jain; Karen K Hirschi; Ai Yamamato; Louis-Eric Trudeau; Massimo Santoro; Martin A Schwartz Journal: J Cell Biol Date: 2022-06-13 Impact factor: 8.077
Authors: Yao Wei Lu; Nina Martino; Brennan D Gerlach; John M Lamar; Peter A Vincent; Alejandro P Adam; John J Schwarz Journal: Arterioscler Thromb Vasc Biol Date: 2021-01-07 Impact factor: 8.311