Angiopoietin-1 Requires Oxidant Signaling through p47phox to Promote Endothelial Barrier Defense

Reactive oxygen species (ROS) are largely considered to be pathogenic to normal endothelial function in disease states such as sepsis. We hypothesized that Angiopoietin-1 (Angpt-1), an endogenous agonist of the endothelial-specific receptor, Tie-2, promotes barrier defense by activating NADPH oxidas...

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Vydáno v:	PloS one Ročník 10; číslo 3; s. e0119577
Hlavní autoři:	Ghosh, Chandra C., Mukherjee, Aditi, David, Sascha, Milam, Katelyn E., Hunter, Jon T., Parikh, Samir M.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 11.03.2015 Public Library of Science (PLoS)
Témata:	Actin Angiogenesis Angiopoietin Angiopoietin-1 - genetics Angiopoietin-1 - metabolism Animals Biology Cells, Cultured Cellular signal transduction Chemical inhibitors Contact stresses Endothelial cells Endothelium Endothelium, Vascular - cytology Endothelium, Vascular - metabolism Gene expression Gene transfer Growth factors Guanosine triphosphatases Guanosinetriphosphatase Humans Hypertension Immunoglobulins Inflammation Intercellular Junctions Kinases Laboratory animals Lipopolysaccharides Lipopolysaccharides - pharmacology Medical research Medical schools Membrane Glycoproteins - antagonists & inhibitors Mice Microvasculature NAD(P)H oxidase NADPH Oxidase 2 NADPH Oxidases - antagonists & inhibitors NADPH Oxidases - genetics NADPH Oxidases - metabolism Nephrology Oxidants Oxidative Stress - drug effects Oxidizing agents Oxygen Permeability Phosphorylation Proteins Rac1 protein Reactive oxygen species Reactive Oxygen Species - metabolism RhoA protein Sepsis Signal transduction Signaling siRNA Thrombin Thrombin - pharmacology Transduction United States
ISSN:	1932-6203, 1932-6203
On-line přístup:	Získat plný text
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Shrnutí:	Reactive oxygen species (ROS) are largely considered to be pathogenic to normal endothelial function in disease states such as sepsis. We hypothesized that Angiopoietin-1 (Angpt-1), an endogenous agonist of the endothelial-specific receptor, Tie-2, promotes barrier defense by activating NADPH oxidase (NOX) signaling. Using primary human microvascular endothelial cells (HMVECs), we found that Angpt-1 stimulation induces phosphorylation of p47phox and a brief oxidative burst that is lost when chemical inhibitors of NOX activity or siRNA against the NOX component p47phox were applied. As a result, there was attenuated ROS activity, disrupted junctional contacts, enhanced actin stress fiber accumulation, and induced gap formation between confluent HMVECs. All of these changes were associated with weakened barrier function. The ability of Angpt-1 to prevent identical changes induced by inflammatory permeability mediators, thrombin and lipopolysaccharides (LPS), was abrogated by p47phox knockdown. P47phox was required for Angpt-1 to activate Rac1 and inhibit mediator-induced activation of the small GTPase RhoA. Finally, Angpt-1 gene transfer prevented vascular leakage in wildtype mice exposed to systemically administered LPS, but not in p47phox knock out (p47-/-) littermates. These results suggest an essential role for NOX signaling in Angpt-1-mediated endothelial barrier defense against mediators of systemic inflammation. More broadly, oxidants generated for signal transduction may have a barrier-promoting role in vascular endothelium.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: SMP advises Vasomune and Eunoia Biotech and Beth Israel Deaconess Medical Center lists SMP as an inventor on disclosures and patents pertaining to angiopoietins. Samir M. Parikh is member of the Editorial Board of PLoS One. Samir M. Parikh declares that Beth Israel Deaconess Medical Center has listed him as an inventor on a patent pertaining to angiopoietins (US 8,685,393). Samir M. Parikh confirms that the competing interests do not alter the authors’ adherence to all PLOS One policies on sharing data and materials regarding this manuscript. Conceived and designed the experiments: AM SD CCG SMP. Performed the experiments: AM SD CCG KEM JTH. Analyzed the data: AM SD CCG KEM SMP. Contributed reagents/materials/analysis tools: AM CCG. Wrote the paper: KEM CCG SMP.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0119577