Distinct roles for I kappa B kinases alpha and beta in regulating pulmonary endothelial angiogenic function during late lung development

Abstract

Pulmonary angiogenesis is essential for alveolarization, the final stage of lung development that markedly increases gas exchange surface area. We recently demonstrated that activation of the nuclear factor kappa-B (NF kappa B) pathway promotes pulmonary angiogenesis during alveolarization. However, the mechanisms activating NF kappa B in the pulmonary endothelium, and its downstream targets are not known. In this study, we sought to delineate the specific roles for the NF kappa B activating kinases, IKK alpha and IKK beta, in promoting developmental pulmonary angiogenesis. Microarray analysis of primary pulmonary endothelial cells (PECs) after silencing IKK alpha or IKK beta demonstrated that the 2 kinases regulate unique panels of genes, with few shared targets. Although silencing IKK alpha induced mild impairments in angiogenic function, silencing IKK beta induced more severe angiogenic defects and decreased vascular cell adhesion molecule expression, an IKK beta regulated target essential for both PEC adhesion and migration. Taken together, these data show that IKK alpha and IKK beta regulate unique genes in PEC, resulting in differential effects on angiogenesis upon inhibition, and identify IKK beta as the predominant regulator of pulmonary angiogenesis during alveolarization. These data suggest that therapeutic strategies to specifically enhance IKK beta activity in the pulmonary endothelium may hold promise to enhance lung growth in diseases marked by altered alveolarization.