Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia

Am J Respir Crit Care Med. 2020 Jul 1;202(1):100-111. doi: 10.1164/rccm.201906-1232OC.


Rationale: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD.Objectives: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or FOXF1 (forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.Methods: Newborn mice were exposed to 75% O2 for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with Foxm1 or Foxf1 cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator.Measurements and Main Results: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood.Conclusions: Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.

Keywords: FOX transcription factors; VEGF signaling; bronchopulmonary dysplasia; nanoparticle gene delivery systems; neonatal hyperoxic lung injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiogenesis Inducing Agents / administration & dosage*
  • Angiogenesis Inducing Agents / pharmacology
  • Angiogenesis Inducing Agents / therapeutic use
  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Drug Delivery Systems*
  • Female
  • Flow Cytometry
  • Forkhead Box Protein M1 / administration & dosage*
  • Forkhead Box Protein M1 / pharmacology
  • Forkhead Box Protein M1 / therapeutic use
  • Forkhead Transcription Factors / administration & dosage*
  • Forkhead Transcription Factors / pharmacology
  • Forkhead Transcription Factors / therapeutic use
  • Hyperoxia / drug therapy*
  • Hyperoxia / pathology
  • Hyperoxia / physiopathology
  • Injections, Intravenous
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Nanoparticles*
  • Pulmonary Alveoli / blood supply
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / pathology
  • Pulmonary Alveoli / physiopathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Treatment Outcome


  • Angiogenesis Inducing Agents
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxf1 protein, mouse
  • Foxm1 protein, mouse