Enhancement of angiogenic effectors through hypoxia-inducible factor in preterm primate lung in vivo

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 291; no. 4; p. 11
• Main Authors: Asikainen, Tiina M, Waleh, Nahid S, Schneider, Barbara K, Clyman, Ronald I, White, Carl W
• Format: Journal Article
• Language: English
• Published: Bethesda American Physiological Society 01.10.2006
• Subjects: Hypoxia; Lungs; Primates; Respiratory diseases
• ISSN: 1040-0605; 1522-1504

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. Pulmonary angiogenic factors were assessed by quantitative real-time PCR, Western blot, and immunohistochemistry in preterm baboons (125 days + 14 days pro re nata O^sub 2^ model) treated for 14 days with intravenous FG-4095, an inhibitor of prolyl hydroxylase domain-containing proteins (PHDs) that initiates HIF degradation. HIF-1α, but not HIF-2α, mRNA and protein were increased (8- 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. These results indicate that HIF stimulation by PHD inhibition enhances lung angiogenesis in the primate model of BPD. [PUBLICATION ABSTRACT]