Endothelial p110γPI3K mediates endothelial regeneration and vascular repair after inflammatory vascular injury

Xiaojia Huang, Zhiyu Dai, Lei Cai, Kai Sun, Jaehyung Cho, Kurt H. Albertine, Asrar B. Malik, Dean E. Schraufnagel, You Yang Zhao*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Background-The integrity of endothelial monolayer is a sine qua non for vascular homeostasis and maintenance of tissuefluid balance. However, little is known about the signaling pathways regulating regeneration of the endothelial barrier after inflammatory vascular injury. Methods and Results-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. Conclusions-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.

Original languageEnglish (US)
Pages (from-to)1093-1103
Number of pages11
JournalCirculation
Volume133
Issue number11
DOIs
StatePublished - 2016

Keywords

  • Endothelial regeneration
  • Endothelium, vascular
  • Inflammation
  • Vascular diseases
  • Vascular repair

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Huang, X., Dai, Z., Cai, L., Sun, K., Cho, J., Albertine, K. H., Malik, A. B., Schraufnagel, D. E., & Zhao, Y. Y. (2016). Endothelial p110γPI3K mediates endothelial regeneration and vascular repair after inflammatory vascular injury. Circulation, 133(11), 1093-1103. https://doi.org/10.1161/CIRCULATIONAHA.115.020918