Disrupted pulmonary artery cyclic guanosine monophosphate signaling in mice with hyperoxia-induced pulmonary hypertension

Keng Jin Lee, Sara K. Berkelhamer, Gina A. Kim, Joann M. Taylor, Kelly M. O'Shea, Robin H Steinhorn, Kathryn N. Farrow

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Pulmonary hypertension (PH) occurs in 25 to 35% of premature infants with significant bronchopulmonary dysplasia (BPD). Neonatal mice exposed to 14 days of hyperoxia develop BPD-like lung injury and PH. To determinne the impact of hyperoxia on pulmonary artery (PA) cyclic guanosine monophosphate (cGMP) signaling in a murine model of lung injury and PH, neonatal C57BL/6 mice were placed in room air, 75% O2 for 14 days (chronic hyperoxia [CH]) or 75% O2 for 24 hours, followed by 13 days of room air (acute hyperoxia with recovery [AHR]) with or without sildenafil. At 14 days, mean alveolar area, PA medial wall thickness (MWT), right ventricular hypertrophy (RVH), and vessel density were assessed. PA protein was analyzed for cGMP, soluble guanylate cyclase, and PDE5 activity. CH and AHR mice had RVH, but only CH mice had increased alveolar area and MWT and decreased vessel density. In CH and AHR PAs, soluble guanylate cyclase activity was decreased, and PDE5 activity was increased. In CH mice, sildenafil attenuated MWT and RVH but did not improve mean alveolar area or vessel density. In CH and AHR PAs, sildenafil decreased PDE5 activity and increased cGMP. Our results indicate that prolonged hyperoxia leads to lung injury, PH, RVH, and disrupted PA cGMP signaling. Furthermore, 24 hours of hyperoxia causes RVH and disrupted PA cGMPsignaling that persists for 13 days. Sildenafil reducedRVHand restored vascular cGMP signaling but did not attenuate lung injury. Thus, hyperoxia can rapidly disrupt PA cGMP signaling in vivo with sustained effects, and concurrent sildenafil therapy can be protective.

Original languageEnglish (US)
Pages (from-to)369-378
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume50
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • Bronchopulmonary dysplasia
  • Phosphodiesterases
  • Right ventricular hypertrophy
  • Soluble guanylate cyclase

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'Disrupted pulmonary artery cyclic guanosine monophosphate signaling in mice with hyperoxia-induced pulmonary hypertension'. Together they form a unique fingerprint.

Cite this