Endothelial p110γPI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury.
Endothelial p110γPI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury.
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DOI：
10.1161/circulationaha.115.020918
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发表时间：
2016-03-15
期刊：
影响因子：
37.8
通讯作者：
Zhao YY
中科院分区：
文献类型：
--
作者：
Huang X;Dai Z;Cai L;Sun K;Cho J;Albertine KH;Malik AB;Schraufnagel DE;Zhao YY
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，对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。采用遗传学和药理学方法，我们证明了内皮再生选择性地需要激活p110γ PI 3 K信号，从而介导内皮修复转录因子FoxM 1的表达。我们观察到，在用p110γ-选择性抑制剂处理的小鼠和LPS攻击后的Pik 3cg −/−小鼠中，肺血管系统中的FoxM 1诱导被抑制。Pik 3cg −/−小鼠表现出脓毒症诱导的持续性肺部炎症和血管通透性的持续增加。Pik 3cg −/−小鼠肺内皮细胞中p110γ或FoxM 1表达的恢复恢复了内皮再生，并使有缺陷的血管修复程序正常化。我们还观察到p110γ在ARDS患者肺血管内皮细胞中的表达减少，表明p110γ-FoxM 1血管修复信号通路受损是该疾病持续性肺微血管渗漏和水肿形成的关键因素。我们确定p110γ是脓毒症诱导的炎症损伤后内皮再生和血管修复的关键介质。因此，激活p110γ-FoxM 1内皮再生可能代表了治疗炎性血管疾病的新策略。
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 following inflammatory vascular injury. Employing 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 FoxM1. We observed that FoxM1 induction in the pulmonary vasculature was inhibited in mice treated with p110γ-selective inhibitor and in Pik3cg−/− mice following LPS 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 ARDS patients, 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 following sepsis-induced inflammatory injury. Thus, activation of p110γ-FoxM1 endothelial regeneration may represent a novel strategy for the treatment of inflammatory vascular diseases.