Xiaojia Huang1, Zhiyu Dai1, Lei Cai1, Kai Sun1, Jaehyung Cho1, Kurt H Albertine1, Asrar B Malik1, Dean E Schraufnagel1, You-Yang Zhao2. 1. 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.). 2. 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.). yyzhao@uic.edu.
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 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.
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 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.
Authors: Jamila Laoukili; Matthijs R H Kooistra; Alexandra Brás; Jos Kauw; Ron M Kerkhoven; Ashby Morrison; Hans Clevers; René H Medema Journal: Nat Cell Biol Date: 2005-01-16 Impact factor: 28.824
Authors: Evan Ong; Xiao-Pei Gao; Dan Predescu; Michael Broman; Asrar B Malik Journal: Am J Physiol Lung Cell Mol Physiol Date: 2005-09-23 Impact factor: 5.464
Authors: You-Yang Zhao; Xiao-Pei Gao; Yidan D Zhao; Muhammad K Mirza; Randall S Frey; Vladimir V Kalinichenko; I-Ching Wang; Robert H Costa; Asrar B Malik Journal: J Clin Invest Date: 2006-09 Impact factor: 14.808
Authors: Xiaojia Huang; Xianming Zhang; David X Zhao; Jun Yin; Guochang Hu; Colin E Evans; You-Yang Zhao Journal: Am J Pathol Date: 2019-05-20 Impact factor: 4.307
Authors: Samriddhi Shukla; David Milewski; Arun Pradhan; Nihar Rama; Kathryn Rice; Tien Le; Matthew J Flick; Sara Vaz; Xueheng Zhao; Kenneth D Setchell; Elsa Logarinho; Vladimir V Kalinichenko; Tanya V Kalin Journal: Mol Cancer Ther Date: 2019-04-30 Impact factor: 6.261
Authors: Zhiyu Dai; Maggie M Zhu; Yi Peng; Hua Jin; Narsa Machireddy; Zhijian Qian; Xianming Zhang; You-Yang Zhao Journal: Am J Respir Crit Care Med Date: 2018-09-15 Impact factor: 21.405