Endothelial-specific loss of IKK beta disrupts pulmonary endothelial angiogenesis and impairs postnatal lung growth

Pulmonary angiogenesis drives alveolarization, but the transcriptional regulators directing pulmonary angiogenesis remain poorly defined. Global, pharmacological inhibition of nuclear factor-kappa B (NF-kappa B) impairs pulmonary angiogenesis and alveolarization. However, establishing a definitive role for NF-kappa B in pulmonary vascular development has been hindered by embryonic lethality induced by constitutive deletion of NF-.B family members. We created a mouse model allowing inducible deletion of the NF-kappa B activator, IKKb, in endothelial cells (ECs) and assessed the effect on lung structure, endothelial angiogenic function, and the lung transcriptome. Embryonic deletion of IKKb permitted lung vascular development but resulted in a disorganized vascular plexus, while postnatal deletion significantly decreased radial alveolar counts, vascular density, and proliferation of both endothelial and nonendothelial lung cells. Loss of IKKb impaired survival, proliferation, migration, and angiogenesis in primary lung ECs in vitro, in association with decreased expression of VEGFR2 and activation of downstream effectors. Loss of endothelial IKKb in vivo induced broad changes in the lung transcriptome with downregulation of genes related to mitotic cell cycle, extracellular matrix (ECM)-receptor interaction, and vascular development, and the upregulation of genes related to inflammation. Computational deconvolution suggested that loss of endothelial IKKb decreased general capillary, aerocyte capillary, and alveolar type I cell abundance. Taken together, these data definitively establish an essential role for endogenous endothelial IKKb signaling during alveolarization. A deeper understanding of the mechanisms directing this developmental, physiological activation of IKKb in the lung vasculature may provide novel targets for the development of strategies to enhance beneficial proangiogenic signaling in lung development and disease. NEW & NOTEWORTHY This study highlights the cell-specific complexity of nuclear factor kappa B signaling in the developing lung by demonstrating that inducible loss of IKK beta in endothelial cells impairs alveolarization, disrupts EC angiogenic function, and broadly represses genes important for vascular development.