Intrauterine growth restriction decreases NF-κB signaling in fetal pulmonary artery endothelial cells of fetal sheep

Abstract

Intrauterine growth restriction (IUGR) in premature newborns increases the risk for bronchopulmonary dysplasia, a chronic lung disease characterized by disrupted pulmonary angiogenesis and alveolarization. We previously showed that experimental IUGR impairs angiogenesis; however, mechanisms that impair pulmonary artery endothelial cell (PAEC) function are uncertain. The NF-κB pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NF-κB-regulated proangiogenic targets in fetal PAEC. PAECs were isolated from the lungs of control fetal sheep and sheep with experimental IUGR from an established model of chronic placental insufficiency. Microarray analysis identified suppression of NF-κB signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4α1 and laminin α4, components of the basement membrane and putative NF-κB targets. In comparison with controls, immunostaining of active NF-κB complexes, NF-κB-DNA binding, baseline expression of NF-κB subunits p65 and p50, and LPS-mediated inducible activation of NF-κB signaling were decreased in IUGR PAEC. Although pharmacological NF-κB inhibition did not affect angiogenic function in IUGR PAEC, angiogenic function of control PAEC was reduced to a similar degree as that observed in IUGR PAEC. These data identify reductions in endothelial NF-κB signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NF-κB-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NF-κB activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR.

Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System

“…They showed decreased NF-κB signaling in pulmonary artery endothelial cells (PAECs) using a sheep model for IUGR (chronic placental insufficiency). Furthermore, remarkable alterations in the expression of extracellular matrix (ECM) pathways, including decreased collagen and laminin, have been detected using microarray analysis [ 12 ].…”

Novel functional role of GH/IGF-I in neonatal lung myofibroblasts and in rat lung growth after intrauterine growth restriction

“…Clinical findings were confirmed in experimental animal models of IUGR, showing an increase of respiratory system resistance and a reduction of lung compliance in adult rats after IUGR (6,7). Along with reduced lung function, lung structural analysis revealed impaired alveolar formation with lung growth arrest and adverse effects of angiogenesis after IUGR (6,28,48,49). Interestingly, recent studies from our group showed that low birth weight and early postnatal reduced alveolar formation after IUGR were followed not only by accelerated postnatal weight gain but also by an alveolar growth (66), as determined by measurement of mean linear intercept as an indicator of alveolarization and quantification of proliferative myofibroblasts.…”

Integrated Analysis of Key Genes and Pathways Involved in Fetal Growth Restriction and Their Associations With the Dysregulation of the Maternal Immune System

“…An altered innate immune system is associated with FGR based on the increased susceptibility to infections in the postnatal period ( Amdi et al, 2020 ). Additionally, the NF-κB pathway contributes to vascular growth in the developing fetal lung, and the maintenance of endothelial NF-κB activation may be useful in FGR marked by disrupted angiogenesis ( Dodson et al, 2018 ). The significantly down-regulated gene HLA–DQA1 encodes a membrane-anchored protein for presenting peptides derived from extracellular proteins.…”