PT - JOURNAL ARTICLE AU - Min Liu AU - Cristiana Iosef AU - Shailaja Rao AU - Racquel Domingo-Gonzalez AU - Sha Fu AU - Paige Snider AU - Simon J. Conway AU - Gray S. Umbach AU - Sarah C. Heilshorn AU - Ruby E. Dewi AU - Mar J. Dahl AU - Donald M. Null AU - Kurt H. Albertine AU - Cristina M. Alvira TI - Developmental Expression of Transforming Growth Factor Induced Protein Promotes NF-Kappa-B Mediated Angiogenesis During Postnatal Lung Development AID - 10.1101/2020.05.28.121871 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.05.28.121871 4099 - http://biorxiv.org/content/early/2020/05/29/2020.05.28.121871.short 4100 - http://biorxiv.org/content/early/2020/05/29/2020.05.28.121871.full AB - Rationale Pulmonary angiogenesis is a key driver of alveolarization. Our prior studies showed that nuclear factor kappa-B (NFκB) promotes pulmonary angiogenesis during early alveolarization. However, the mechanisms regulating temporal-specific NFκB activation in the pulmonary vasculature are unknown.Objectives To identify mechanisms that activate pro-angiogenic NFκB signaling in the developing pulmonary vasculature.Methods Proteomic analysis of the lung secretome was performed using 2D-DIGE. NFκB activation and angiogenic function was assessed in primary pulmonary endothelial cells (PEC) and TGFBI-regulated genes identified using RNA-sequencing. Alveolarization and pulmonary angiogenesis was assessed in WT and TGFBI null mice exposed to normoxia or hyperoxia. Lung TGFBI expression was determined in premature lambs supported by invasive and noninvasive respiratory support.Measurements and Main Results Secreted factors from the early alveolar, but not the late alveolar or adult lung, promoted proliferation and migration in quiescent, adult PEC. Proteomic analysis identified transforming growth factor beta-induced protein (TGFBI) as a protein highly expressed by myofibroblasts in the early alveolar lung that promoted PEC migration by activating NFκB via αvβ3 integrins. RNA-sequencing identified Csf3 as a TGFBI-regulated gene that enhances nitric oxide production in PEC. Loss of TGFBI in mice exaggerated the impaired pulmonary angiogenesis induced by chronic hyperoxia, and TGFBI expression was disrupted in premature lambs with impaired alveolarization.Conclusions Our studies identify TGFBI as a developmentally-regulated protein that promotes NFκB-mediated angiogenesis during early alveolarization by enhancing nitric oxide production. We speculate that dysregulation of TGFBI expression may contribute to diseases marked by impaired alveolar and vascular growth.Competing Interest StatementThe authors have declared no competing interest.