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 O2 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% O2. Both groups of preterm animals developed lung hypoplasia similar to human BPD. Expression of HIF‐1α protein by Western blotting of nuclear extracts of fetal baboon samples differed from that of HIF‐2α in that both were high at early third trimester, but at term, HIF‐1α was absent, whereas HIF‐2α 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‐1α was diminished both in 125‐day and 140‐day BPD models, whereas HIF‐2α 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‐1α and/or HIF‐2α 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. Pediatr Pulmonol. © 2005 Wiley‐Liss, Inc.