Huang Xiaojia, Dai Zhiyu, Cai Lei, Sun Kai, Cho Jaehyung, Albertine Kurt H, Malik Asrar B, Schraufnagel Dean E, Zhao You-Yang
From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
Circulation. 2016 Mar 15;133(11):1093-103. doi: 10.1161/CIRCULATIONAHA.115.020918. Epub 2016 Feb 2.
The integrity of endothelial monolayer is a sine qua non for vascular homeostasis and maintenance of tissue-fluid balance. However, little is known about the signaling pathways regulating regeneration of the endothelial barrier after inflammatory vascular injury.
Using genetic and pharmacological approaches, we demonstrated that endothelial regeneration selectively requires activation of p110γPI3K signaling, which thereby mediates the expression of the endothelial reparative transcription factor Forkhead box M1 (FoxM1). We observed that FoxM1 induction in the pulmonary vasculature was inhibited in mice treated with a p110γ-selective inhibitor and in Pik3cg(-/-) mice after lipopolysaccharide challenge. Pik3cg(-/-) mice exhibited persistent lung inflammation induced by sepsis and sustained increase in vascular permeability. Restoration of expression of either p110γ or FoxM1 in pulmonary endothelial cells of Pik3cg(-/-) mice restored endothelial regeneration and normalized the defective vascular repair program. We also observed diminished expression of p110γ in pulmonary vascular endothelial cells of patients with acute respiratory distress syndrome, suggesting that impaired p110γ-FoxM1 vascular repair signaling pathway is a critical factor in persistent leaky lung microvessels and edema formation in the disease.
We identify p110γ as the critical mediator of endothelial regeneration and vascular repair after sepsis-induced inflammatory injury. Thus, activation of p110γ-FoxM1 endothelial regeneration may represent a novel strategy for the treatment of inflammatory vascular diseases.
内皮单层的完整性是血管稳态和维持组织液平衡的必要条件。然而，关于炎症性血管损伤后调节内皮屏障再生的信号通路知之甚少。
我们使用基因和药理学方法证明，内皮再生选择性地需要p110γPI3K信号的激活，从而介导内皮修复转录因子叉头框M1（FoxM1）的表达。我们观察到，在用p110γ选择性抑制剂处理的小鼠以及脂多糖攻击后的Pik3cg(-/-)小鼠中，肺血管中FoxM1的诱导受到抑制。Pik3cg(-/-)小鼠表现出由败血症诱导的持续性肺部炎症和血管通透性的持续增加。在Pik3cg(-/-)小鼠的肺内皮细胞中恢复p110γ或FoxM1的表达可恢复内皮再生并使有缺陷的血管修复程序正常化。我们还观察到急性呼吸窘迫综合征患者肺血管内皮细胞中p110γ的表达减少，这表明受损的p110γ-FoxM1血管修复信号通路是该疾病中肺微血管持续渗漏和水肿形成的关键因素。
我们确定p110γ是败血症诱导的炎症性损伤后内皮再生和血管修复的关键介质。因此，激活p110γ-FoxM1内皮再生可能代表一种治疗炎症性血管疾病的新策略。
