Hyperoxia disrupts extracellular signal-regulated kinases 1/2-induced angiogenesis in the developing lungs

Renuka T. Menon, Amrit Kumar Shrestha, Roberto Barrios, Binoy Shivanna

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number1525
JournalInternational journal of molecular sciences
Volume19
Issue number5
DOIs
StatePublished - May 20 2018

Keywords

  • Angiogenesis
  • Bronchopulmonary dysplasia
  • Cell cycle
  • Extracellular signal-regulated kinases 1/2
  • HPAECs
  • Hyperoxia

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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