title: IKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways.
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.
authors.affiliation: The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. nashida@kuhp.kyoto-u.ac.jp
authors.forename: Noboru
authors.initials: N
authors.lastname: Ashida
authors.forename: Sucharita
authors.initials: S
authors.lastname: Senbanerjee
authors.forename: Shohta
authors.initials: S
authors.lastname: Kodama
authors.forename: Shi Yin
authors.initials: SY
authors.lastname: Foo
authors.forename: Matthew
authors.initials: M
authors.lastname: Coggins
authors.forename: Joel A
authors.initials: JA
authors.lastname: Spencer
authors.forename: Parisa
authors.initials: P
authors.lastname: Zamiri
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Shen
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Tracey
authors.initials: T
authors.lastname: Sciuto
authors.forename: Ann
authors.initials: A
authors.lastname: Dvorak
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
mesh_terms: D000818:Animals; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D005260:Female; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase