Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/ijms19051525
Keywords
extracellular signal-regulated kinases 1/2; hyperoxia; bronchopulmonary dysplasia; HPAECs; angiogenesis; cell cycle
Funding
- National Institutes of Health [HD-073323, P30DK056338]
- American Heart Association [BGIA-20190008]
- American Lung Association [RG-349917]
- Texas Children's Hospital Pediatric Pilot Award program
Ask authors/readers for more resources
Hyperoxia contributes to the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of infants that is characterized by interrupted alveologenesis. Disrupted angiogenesis inhibits alveologenesis, but the mechanisms of disrupted angiogenesis in the developing lungs are poorly understood. In pre-clinical BPD models, hyperoxia increases the expression of extracellular signal-regulated kinases (ERK) 1/2; however, its effects on the lung endothelial ERK1/2 signaling are unclear. Further, whether ERK1/2 activation promotes lung angiogenesis in infants is unknown. Hence, we tested the following hypotheses: (1) hyperoxia exposure will increase lung endothelial ERK1/2 signaling in neonatal C57BL/6J (WT) mice and in fetal human pulmonary artery endothelial cells (HPAECs); (2) ERK1/2 inhibition will disrupt angiogenesis in vitro by repressing cell cycle progression. In mice, hyperoxia exposure transiently increased lung endothelial ERK1/2 activation at one week of life, before inhibiting it at two weeks of life. Interestingly, hyperoxia-mediated decrease in ERK1/2 activation in mice was associated with decreased angiogenesis and increased endothelial cell apoptosis. Hyperoxia also transiently activated ERK1/2 in HPAECs. ERK1/2 inhibition disrupted angiogenesis in vitro, and these effects were associated with altered levels of proteins that modulate cell cycle progression. Collectively, these findings support our hypotheses, emphasizing that the ERK1/2 pathway is a potential therapeutic target for BPD infants with decreased lung vascularization.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available