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Lipopolysaccharide (LPS)-mediated angiopoietin-2-dependent autocrine angiogenesis is regulated by NADPH oxidase 2 (Nox2) in human pulmonary microvascular endothelial cells. J Biol Chem 2015 Feb 27;290(9):5449-61

Date

01/09/2015

Pubmed ID

25568324

Pubmed Central ID

PMC4342461

DOI

10.1074/jbc.M114.600692

Scopus ID

2-s2.0-84923766524   38 Citations

Abstract

Sepsis-mediated endothelial Angiopoeitin-2 (Ang2) signaling may contribute to microvascular remodeling in the developing lung. The mechanisms by which bacterial cell wall components such as LPS mediate Ang2 signaling in human pulmonary microvascular endothelial cells (HPMECs) remain understudied. In HPMEC, LPS-induced Ang2, Tie2, and VEGF-A protein expression was preceded by increased superoxide formation. NADPH oxidase 2 (Nox2) inhibition, but not Nox4 or Nox1 inhibition, attenuated LPS-induced superoxide formation and Ang2, Tie2, and VEGF-A expression. Nox2 silencing, but not Nox4 or Nox1 silencing, inhibited LPS-mediated inhibitor of κ-B kinase β (IKKβ) and p38 phosphorylation and nuclear translocation of NF-κB and AP-1. In HPMECs, LPS increased the number of angiogenic tube and network formations in Matrigel by >3-fold. Conditioned media from LPS-treated cells also induced angiogenic tube and network formation in the presence of Toll-like receptor 4 blockade but not in the presence of Ang2 and VEGF blockade. Nox2 inhibition or conditioned media from Nox2-silenced cells attenuated LPS-induced tube and network formation. Ang2 and VEGF-A treatment rescued angiogenesis in Nox2-silenced cells. We propose that Nox2 regulates LPS-mediated Ang2-dependent autocrine angiogenesis in HPMECs through the IKKβ/NF-κB and MAPK/AP-1 pathways.

Author List

Menden H, Welak S, Cossette S, Ramchandran R, Sampath V

Authors

Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin
Scott R. Welak MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Active Transport, Cell Nucleus
Angiopoietin-2
Animals
Cells, Cultured
Endothelial Cells
Gene Expression
Humans
I-kappa B Kinase
Immunoblotting
Lipopolysaccharides
Lung
Membrane Glycoproteins
Mice, Inbred C57BL
Microscopy, Fluorescence
Microvessels
NADPH Oxidase 2
NADPH Oxidases
NF-kappa B
Neovascularization, Physiologic
Phosphorylation
RNA Interference
Receptor, TIE-2
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Transcription Factor AP-1
Vascular Endothelial Growth Factor A
p38 Mitogen-Activated Protein Kinases
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d