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Intrauterine growth restriction decreases NF-?B 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-?B pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NF-?B-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-?B signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4?1 and laminin ?4, components of the basement membrane and putative NF-?B targets. In comparison with controls, immunostaining of active NF-?B complexes, NF-?B-DNA binding, baseline expression of NF-?B subunits p65 and p50, and LPS-mediated inducible activation of NF-?B signaling were decreased in IUGR PAEC. Although pharmacological NF-?B 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-?B signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NF-?B-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NF-?B activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR.

SUBMITTER: Dodson RB 

PROVIDER: S-EPMC6172617 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Dodson R Blair RB   Powers Kyle N KN   Gien Jason J   Rozance Paul J PJ   Seedorf Gregory G   Astling David D   Jones Kenneth K   Crombleholme Timothy M TM   Abman Steven H SH   Alvira Cristina M CM  

American journal of physiology. Lung cellular and molecular physiology 20180503 3


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 pro  ...[more]

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