Effect of preterm birth on hypoxia-inducible factors and vascular endothelial growth factor in primate lungs

Diminished vascular and alveolar development is characteristic of bronchopulmonary dysplasia (BPD). The low fetal O-2 tension promotes angiogenic responses during ontogenesis, while preterm birth interrupts normal lung growth. Most of the angiogenic responses are governed by hypoxia-inducible factors (HIFs), the expressions of which are unknown in the lungs of preterm primates. Lung tissue was harvested from fetal third-trimester baboons as well as from preterm baboons (67% or 75% of term gestation) treated with mechanical ventilation and either pro re nata (PRN) or 100% O-2. Both groups of preterm animals developed lung hypoplasia similar to human BPD. Expression of HIF-1 alpha protein by Western blotting of nuclear extracts of fetal baboon samples differed from that of HIF-2 alpha in that both were high at early third trimester, but at term, HIF-1 alpha was absent, whereas HIF-2 alpha remained unchanged. Moreover, the expression of prolyl hydroxylase domain-containing proteins 2 and 3 (PHD-2 and -3), which degrade HIFs, was increased following term birth. HIF-1 alpha was diminished both in 125-day and 140-day BPD models, whereas HIF-2 alpha was reduced only in the latter. Surprisingly, vascular endothelial growth factor (VEGF) was enhanced in preterm baboons with BPD as compared with age-matched fetal controls, and there was a negative correlation between HIF-1 alpha and/or HIF-2 alpha and VEGF in BPD. Moreover, VEGF receptors KDR and/ or Flt-1 were decreased in BPD. Preterm birth also prevented the end-gestational increase in the expression of endothelial cell marker platelet-endothelial cell adhesion molecule 1. These results suggest that selective downregulation of HIFs in lungs of preterm neonates may contribute to the pathophysiology of BPD.