IKK\(\beta\) 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)- (\kappa)B 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 IKK(\beta), the primary kinase mediating NF-(\kappa)B activation, are smaller than littermates and born at less than the expected Mendelian frequency in association with hypotrophic and hypovascular placentae. IKK(\beta) -deleted endothelium manifests increased vascular permeability and reduced migration. Surprisingly, we find that these defects result from loss of kinase-independent effects of IKK(\beta) on activation of the serine-threonine kinase, Akt. Together, these data demonstrate essential roles for IKK(\beta) in regulating endothelial permeability and migration, as well as an unanticipated connection between IKK(\beta) and Akt signalling.