Abstract
Background: Neonatal chronic lung disease (CLD) is characterized by impaired lung development, leading to oxygen dependency and vascular remodeling. We investigated the role of the bone morphogenetic protein receptor 2 (BMPR2) signaling pathway which is critical for vascular development in a mouse model of CLD. We hypothesized that the BMPR2 activator FK506, recently found to reduce endothelial apoptosis and increase endothelial tube formation, might be beneficial in neonatal CLD.
Methods: In a mouse model of CLD, 5-6 day old C57B6 mice were mechanically ventilated for 2h and 8h with 40% oxygen (MV-O2) and compared to non-ventilated controls (n=4/group). Protein expression of phosphoSmad1/5/8 as well as Id1, a downstream target of BMPR2, was measured in whole lung lysates by western-immunoblotting. In vitro, human fetal endothelial cells (ECs) were exposed to 40% hyperoxia for 24 h and treated with BMP6, FK506, TGF beta or the combination of both (n=3 each group). BMPR2 and Id1 expression were assessed by qRT-PCR.
Results: MV-O2 for 8h significantly reduced phosphoSmad1/5/8 as well as Id1 protein expression in total lung lysates (p< 0.01). In line with this, hyperoxia significantly decreased BMPR2 as well as Id1 mRNA expression in human fetal ECs. This effect was prevented by BMP6 treatment, leading to a 2- to 4-fold increase in BMPR2 and Id1 mRNA expression. FK506 partially restored BMPR2 and fully restored Id1 mRNA expression with more pronounced effects in the presence of TGF beta.
Conclusion: Modulating BMPR2 signaling in neonatal CLD might be a promising strategy to improve impaired vasculogenesis in the course of the disease.
- © 2014 ERS