IKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways

Noboru Ashida (), Sucharita SenBanerjee, Shohta Kodama, Shi Yin Foo, Matthew Coggins, Joel A. Spencer, Parisa Zamiri, Dongxiao Shen, Ling Li, Tracey Sciuto, Ann Dvorak, Robert E. Gerszten, Charles P. Lin, Michael Karin and Anthony Rosenzweig ()
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Noboru Ashida: The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Sucharita SenBanerjee: The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Shohta Kodama: Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital, Harvard Medical School
Shi Yin Foo: The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Matthew Coggins: The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Joel A. Spencer: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH), Harvard Medical School
Parisa Zamiri: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH), Harvard Medical School
Dongxiao Shen: Center for Immunology and Inflammatory Diseases MGH, Harvard Medical School
Ling Li: The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
Tracey Sciuto: Beth Israel Deaconess Medical Center, Harvard Medical School
Ann Dvorak: Beth Israel Deaconess Medical Center, Harvard Medical School
Robert E. Gerszten: MGH, Harvard Medical School
Charles P. Lin: Wellman Center for Photomedicine, Massachusetts General Hospital (MGH), Harvard Medical School
Michael Karin: UCSD
Anthony Rosenzweig: The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: Abstract Vascular endothelium provides a selective barrier between the blood and tissues, participates in wound healing and angiogenesis, and regulates tissue recruitment of inflammatory cells. Nuclear factor (NF)-κB transcription factors are pivotal regulators of survival and inflammation, and have been suggested as potential therapeutic targets in cancer and inflammatory diseases. Here we show that mice lacking IKKβ, the primary kinase mediating NF-κB activation, are smaller than littermates and born at less than the expected Mendelian frequency in association with hypotrophic and hypovascular placentae. IKKβ-deleted endothelium manifests increased vascular permeability and reduced migration. Surprisingly, we find that these defects result from loss of kinase-independent effects of IKKβ on activation of the serine-threonine kinase, Akt. Together, these data demonstrate essential roles for IKKβ in regulating endothelial permeability and migration, as well as an unanticipated connection between IKKβ and Akt signalling.

Date: 2011
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DOI: 10.1038/ncomms1317

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