Bronchopulmonary dysplasia (BPD) is the most common and serious chronic
lung disease of preterm infants. The development of
pulmonary hypertension (PH) significantly increases the mortality and morbidity of this disease. β-
Catenin signaling plays an important role in tissue development and remodeling. Aberrant β-
catenin signaling is associated with clinical and experiment models of BPD. To test the hypothesis that inhibition of β-
catenin signaling is beneficial in promoting alveolar and vascular development and preventing PH in experimental BPD, we examined the effects of
ICG001, a newly developed pharmacological inhibitor of β-
catenin, in preventing
hyperoxia-induced BPD in neonatal rats. Newborn rat pups were randomized at postnatal day (
P)2 to room air (RA) +
DMSO (placebo), RA +
ICG001, 90% FiO2 (O2) +
DMSO, or O2 +
ICG001.
ICG001 (10 mg/kg) or
DMSO was given by daily
intraperitoneal injection for 14 days during continuous exposure to RA or
hyperoxia. Primary human pulmonary arterial smooth muscle cells (PASMCs) were cultured in RA or
hyperoxia (95% O2) in the presence of
DMSO or
ICG001 for 24 to 72 hours. Treatment with
ICG001 significantly increased alveolarization and reduced pulmonary
vascular remodeling and PH during
hyperoxia. Furthermore, administering
ICG001 decreased PASMC proliferation and expression of extracellular matrix remodeling molecules in vitro under
hyperoxia. Finally, these structural, cellular, and molecular effects of
ICG001 were associated with down-regulation of multiple β-
catenin target genes. These data indicate that β-
catenin signaling mediates
hyperoxia-induced alveolar impairment and PH in neonatal animals. Targeting β-
catenin may provide a novel strategy to alleviate BPD in preterm infants.