| First Author | Rao S | Year | 2023 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 325 |
| Issue | 3 | Pages | L299-L313 |
| PubMed ID | 37310763 | Mgi Jnum | J:344971 |
| Mgi Id | MGI:7517080 | Doi | 10.1152/ajplung.00034.2023 |
| Citation | Rao S, et al. (2023) Endothelial-Specific Loss of IKKbeta Disrupts Pulmonary Endothelial Angiogenesis and Impairs Postnatal Lung Growth. Am J Physiol Lung Cell Mol Physiol |
| abstractText | Pulmonary angiogenesis drives alveolarization, but the transcriptional regulators directing pulmonary angiogenesis remain poorly defined. Global, pharmacologic inhibition of nuclear factor-kappa B (NFkappaB) impairs pulmonary angiogenesis and alveolarization. However, establishing a definitive role for NFkappaB in pulmonary vascular development has been hindered by embryonic lethality induced by constitutive deletion of NFkappaB family members. We created a mouse model allowing inducible deletion of the NFkappaB activator, IKKbeta, in endothelial cells (EC) and assessed the effect on lung structure, endothelial angiogenic function, and the lung transcriptome. Embryonic deletion of IKKbeta 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 non-endothelial lung cells. Loss of IKKbeta impaired survival, proliferation, migration, and angiogenesis in primary lung EC in vitro, in association with decreased expression of VEGFR2 and activation of downstream effectors. Loss of endothelial IKKbeta in vivo induced broad changes in the lung transcriptome with down-regulation of genes related to mitotic cell cycle, ECM-receptor interaction, and vascular development, and the up-regulation of genes related to inflammation. Computational deconvolution suggested that loss of endothelial IKKbeta decreased general capillary, aerocyte capillary, and alveolar type I cell abundance. Taken together, these data definitely establish an essential role for endogenous endothelial IKKbeta signaling during alveolarization. A deeper understanding of the mechanisms directing this developmental, physiologic activation of IKKbeta in the lung vasculature may provide novel targets for the development of strategies to enhance beneficial pro-angiogenic signaling in lung development and disease. |
