Mechanisms of platelet-derived growth factor-BB regulation of hypoxia-inducible factor-1α expression in pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension / 中国新生儿科杂志

ABSTRACT

Methods:A total of 160 Wistar neonatal rats were assigned into normoxia group, HPH group, normoxia+PDGF-BB group, HPH+PDGF-BB group and HPH+PDGF-BB inhibitor (STI571) group using random number table method (32 rats in each group), each group was further assigned into 4 subgroups on d3, d7, d14 and d21 (8 rats in each subgroup). HPH model was established using nitrogen-oxygen mixture with an oxygen concentration of 10%±0.5%. PDGF-BB groups were injected with adenovirus encoding PDGF-BB in the tail vein. HPH+STI571 group was given STI571 intragastrically. On d3, d7, d14 and d21 after modeling, mean right ventricular systolic pressure (RVSP) was examined. Morphological changes of small pulmonary arteries were observed using HE staining and indicators of pulmonary vascular remodeling calculated. Immunohistochemistry was used to determine the protein levels of PDGF-BB, HIF-1α and proliferation-associated protein nuclear protein Ki67 in the pulmonary vasculature of each group. RT-qPCR was used to determine the mRNA levels of PDGF-BB, HIF-1α and Ki67 in lung tissue.Results:At all time points, RVSP was higher in the HPH group than the normoxia group ( P<0.05), higher in the HPH+PDGF-BB group than the HPH group ( P<0.05), and lower in the HPH+STI571 group than both the HPH+PDGF-BB group and the HPH group ( P<0.05). On d3 after modeling, pulmonary vascular remodeling occurred in the HPH+PDGF-BB group; on d7, pulmonary vascular remodeling occurred in the PDGF-BB group and the HPH group. Pulmonary vascular remodeling appeared later and to a lesser extent in the HPH+STI571 group than the other hypoxic groups. On d3, d7 and d21 after modeling, protein and mRNA levels of PDGF-BB, HIF-1α and Ki67 in the HPH+PDGF-BB group were higher than the other groups ( P<0.05). The protein and mRNA expression levels of PDGF-BB, HIF-1α and Ki67 in the HPH+STI571 group were lower than the HPH+PDGF-BB group and the HPH group at all timepoints ( P<0.05). Conclusions:PDGF-BB up-regulates HIF-1α expression, participates in PASMC proliferation, exacerbates pulmonary vascular remodeling and increases pulmonary artery pressure in neonatal rats with HPH.ObiectiveTo study the roles of platelet-derived growth factor-BB (PDGF-BB) in hypoxic pulmonary hypertension (HPH) and the mechanisms of regulating hypoxia-inducible factor-1α (HIF-1α) expression, promoting the proliferation of pulmonary arterial smooth muscle cells (PASMC) and participating in the remodeling of pulmonary vessels.