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1 Pediatrics, National Jewish Medical & Research Center, Denver, Colorado, United States
2 SRI International, Menlo Park, California, United States
3 Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States; SRI International, Menlo Park, California, United States
* To whom correspondence should be addressed. E-mail: whitec{at}njc.org.
Rationale: Development of lung microvasculature is critical for distal airway formation. Both processes are arrested in the lungs of preterm newborns with bronchopulmonary dysplasia (BPD), a chronic form of lung disease. We hypothesized that activation of hypoxia-inducible factors (HIFs) augments lung vascular development. Objectives, Methods: Pulmonary angiogenic factors were assessed by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry in preterm baboons (125d+14 d pro re nata O2 model) treated for 14 d with intravenous FG-4095, an inhibitor of prolyl hydroxylase domain-containing proteins (PHDs) which initiate HIF degradation. Main Results: HIF-1
, but not HIF-2, mRNA and protein were increased (8-fold and 3-fold, respectively) in FG-4095 treated baboons relative to untreated controls. Expression of PHD-1, -2, and -3 was unchanged. Of note, mRNA and/or protein for platelet-endothelial cell adhesion molecule 1 (PECAM-1) and vascular endothelial growth factor (VEGF) were increased by FG-4095. Moreover, PECAM-1 expressing capillary endothelial cells detected by immunohistochemistry were augmented in FG-4095 treated baboons to levels comparable to those in fetal age-matched controls. Alveolar septal cell expression of Ki67, a proliferative marker, and VEGF were similar in untreated controls and FG-4095 treated neonates. Conclusions: These results indicate that HIF stimulation by PHD inhibition enhances lung angiogenesis in the primate model of BPD.
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