Endothelial p110γPI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury

Abstract

Background 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. Methods and Results 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. Conclusions 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.

Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: A translational mouse model of acute respiratory distress syndrome

“…( Fig 1A ). To determine alterations in lung vascular permeability, we employed the EBA assay to assess pulmonary transvascular flux of Evans blue-conjugated albumin [14, 15]. As shown in Fig 1B in oil-free mice, we observed a marked increase in EBA flux that peaked at 24 hours post-LPS challenge (4mg/kg, i.p.)…”

“…Next we assayed whether the levels of lung inflammation would be similarly affected by the addition of corn oil to LPS-treated mice, by measuring MPO activity, an indicator of neutrophil infiltration [14, 15]. In oil-free mice, lung MPO activity was markedly increased at 12 hours post-LPS challenge, and returned to basal levels at 72 hours post-LPS ( Fig 2A ), which is a pattern of change that is commonly seen in i.p.…”

“…In oil-free mice, lung MPO activity was markedly increased at 12 hours post-LPS challenge, and returned to basal levels at 72 hours post-LPS ( Fig 2A ), which is a pattern of change that is commonly seen in i.p. LPS-induced models of acute lung injury [14, 15]. In oil-loaded mice, however, MPO activity gradually increased and peaked at 48 hours post-LPS, and did not return to basal levels even at 15 days after LPS challenge ( Fig 2A ).…”

“…It has been shown that EC proliferation plays an important role in endothelial repair after inflammatory lung injury following sepsis challenge [13, 15]. To determine cell proliferation in mouse lungs, mice were administered with BrdU at 6 hours prior to tissue collection and proliferating cells were detected by anti-BrdU immunostaining.…”

“…LPS alone commonly peaks in as little as 4–12 hours post-LPS, and fully recovers within 3 days [14, 15, 22]. The pulmonary inflammatory response in human ARDS, however, is most intense for the initial 3 days following disease onset [23, 24].…”