From the Inserm U1034, Biology of Cardiovascular Diseases, CHU de Bordeaux, Pessac, France (C. Caradu, T.C., C. Chapouly, S.G., P.-L.H., E.D., A.-P.G., M.-A.R.).
Service de Médecine Vasculaire, CHU de Toulouse, France (A.B.-R.).
Circ Res. 2018 Oct 12;123(9):1053-1065. doi: 10.1161/CIRCRESAHA.118.313177.
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.
Klf（kruppel 样因子）2 对于建立和维持内皮完整性至关重要。
因此，确定 Klf2 的上游和下游介质将为心血管疾病管理中的替代治疗靶点提供线索。
在这里，我们确定 Dhh（沙漠刺猬）是 Klf2 的下游效应物，其在血管内皮细胞（EC）中的表达受到剪切力的上调和炎症细胞因子的下调。因此，我们表明，EC 中 Dhh 的敲低会促进内皮通透性和 EC 的激活，而 Dhh 激动剂可预防 TNF-α（肿瘤坏死因子-α）或葡萄糖诱导的 EC 功能障碍。此外，我们证明，与糖尿病和炎症相关的严重肢体缺血等病理状况与主要 EC 功能障碍有关。通过在糖尿病小鼠中重现严重肢体缺血的复杂模型，我们发现 Dhh-信号激动剂可显著改善 EC 功能而不促进血管生成，从而改善肌肉灌注。
恢复 EC 功能可显著改善严重肢体缺血的恢复。Dhh 似乎是 Klf2 下游的一个有前途的靶点，可预防与缺血性血管疾病相关的内皮功能障碍。
