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

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  • Noboru Ashida

    (The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
    Present addresses: Department of Clinical Innovative Medicine, Translational Research Center, Kyoto University Faculty of Medicine, Kyoto 606-8507, Japan (N.A.); Department of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (S.S.); Department of Regenerative Medicine and Transplantation, Fukuoka University Faculty of Medicine, Fukuoka 814-0180, Japan (S.K.); Cardiovascular Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA (S.Y.F.); Arsenal Medical, Watertown, Massachusetts 02472, USA (P.Z.).)

  • Sucharita SenBanerjee

    (The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
    Present addresses: Department of Clinical Innovative Medicine, Translational Research Center, Kyoto University Faculty of Medicine, Kyoto 606-8507, Japan (N.A.); Department of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (S.S.); Department of Regenerative Medicine and Transplantation, Fukuoka University Faculty of Medicine, Fukuoka 814-0180, Japan (S.K.); Cardiovascular Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA (S.Y.F.); Arsenal Medical, Watertown, Massachusetts 02472, USA (P.Z.).)

  • Shohta Kodama

    (Tissue Engineering and Regenerative Medicine, Brigham and Women's Hospital, Harvard Medical School
    Present addresses: Department of Clinical Innovative Medicine, Translational Research Center, Kyoto University Faculty of Medicine, Kyoto 606-8507, Japan (N.A.); Department of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (S.S.); Department of Regenerative Medicine and Transplantation, Fukuoka University Faculty of Medicine, Fukuoka 814-0180, Japan (S.K.); Cardiovascular Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA (S.Y.F.); Arsenal Medical, Watertown, Massachusetts 02472, USA (P.Z.).)

  • Shi Yin Foo

    (The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
    MGH, Harvard Medical School
    Present addresses: Department of Clinical Innovative Medicine, Translational Research Center, Kyoto University Faculty of Medicine, Kyoto 606-8507, Japan (N.A.); Department of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (S.S.); Department of Regenerative Medicine and Transplantation, Fukuoka University Faculty of Medicine, Fukuoka 814-0180, Japan (S.K.); Cardiovascular Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA (S.Y.F.); Arsenal Medical, Watertown, Massachusetts 02472, USA (P.Z.).)

  • 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
    Present addresses: Department of Clinical Innovative Medicine, Translational Research Center, Kyoto University Faculty of Medicine, Kyoto 606-8507, Japan (N.A.); Department of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (S.S.); Department of Regenerative Medicine and Transplantation, Fukuoka University Faculty of Medicine, Fukuoka 814-0180, Japan (S.K.); Cardiovascular Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA (S.Y.F.); Arsenal Medical, Watertown, Massachusetts 02472, USA (P.Z.).)

  • 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
    Center for Immunology and Inflammatory Diseases 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)

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.

Suggested Citation

  • 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 & Ch, 2011. "IKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1317
    DOI: 10.1038/ncomms1317
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