Role of Angiogenesis and VEGF in Lung Development, Homeostasis, and Pulmonary Hypertension
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To explore the role of the vasculature in postnatal lung morphogenesis, we examined the role of vascular endothelial growth factor (VEGF) in the newborn lung. The rationale for studying loss of VEGF function in the newborn was:
- that reductions in VEGF had been associated with BPD; and
- that VEGF is major growth factor in vascular development.
However, since knock-out of the VEGF gene is fetal lethal, the role of VEGF in the neonatal and adult lung was unclear. To address these questions we used a VEGF receptor inhibitor (SU5416) to block VEGF-driven angiogenesis in the lungs of neonatal rats. The VEGF receptor blocker, as well as other anti-angiogenic agents (fumigillin, thalidomide) disrupted both vascular and alveolar morphogenesis demonstrating a requirement for angiogenesis in postnatal phase of alveolar development (Jakkula et al. 2000).
Following this study we transiently inhibited VEGF signaling using a single dose of the VEGF receptor blocker. Pulmonary vascular morphogenesis (figure 1), and alveologenesis (figure 2) were still significantly impaired and the rats developed severe pulmonary hypertension (Le Cras et al. 2002). These studies demonstrated a critical role for VEGF in the neonatal lung and suggested that even transient alterations in VEGF signaling might contribute to neonatal lung disease. They also demonstrated the necessity of angiogenesis for normal alveologenesis to occur in the developing lung.
References
Jakkula, M, TD Le Cras, S Gebb, KP Hirth, RM Tuder, NF Voelkel, and SH Abman. (2000) Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am. J. Physiol. (Lung Cell Mol. Physiol.) 279: L600-607
Le Cras, TD, N Markham, R Tuder, NF Voelkel, and SH Abman. (2002) Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure. Am. J. Physiol. (Lung Cell Mol. Physiol.) 283: L555-L562
Contact Information
Tim D. Le Cras PhD
Associate Professor of Pediatrics
Division of Pulmonary Biology
Cincinnati Children's Hospital Medical Center
3333 Burnet Ave., Cincinnati, Ohio 45229-3039
Phone: 513-636-8151
Fax: 513-636-7868
Email: tim.lecras@cchmc.org
