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Published ahead of print on February 18, 2005, doi:10.1165/rcmb.2004-0287OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 5, May 2005, 420-427

A more recent version of this article appeared on May 1, 2005
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Submitted on September 13, 2004
Revised on February 18, 2005

VEGF Receptor 2 Blockade Disrupts Postnatal Lung Development

Sharon A McGrath-Morrow1*, Cecilia Cho1, Chung Cho2, Lijie Zhen2, Daniel J Hicklin3, and Rubin M Tuder4

1 Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA, 2 Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA, 3 Imclone Systems Incorporated, New York, NY, USA, 4 Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: smorrow{at}jhmi.edu.

Vascular endothelial growth factor (VEGF) is necessary for normal postnatal lung development and may underlie the structural lung damage that follows hyperoxic exposure. To determine the individual roles of VEGF receptors (VEGFR) 2 and 1 on postnatal lung growth, neonatal mice were treated with neutralizing antibodies to VEGFR-2 (DC101) or VEGFR-1 (MF1) in the perinatal period. At one week of age, mice treated with DC101 on days two and four of life, had significantly larger mean alveolar diameters (MADs) consistent with impaired alveolization. By two weeks of age, however, perinatally treated DC101mice had normal appearing alveolar structure. Mice exposed to perinatal hyperoxia (O2) also had larger MADs at one week of age, but unlike DC101-treated mice, their mitotic index was decreased at one week of age and they had persistent alveolar enlargement beyond the first two weeks of life. The O2-treated lung also had an increase in caspase 3 at one week of age and significantly greater expression of nitrotyrosine at two weeks of age. Therefore VEGFR-2 blockade in the perinatal period disrupts early alveolar development but the effect is reversible with time, whereas hyperoxic lung injury is associated with ongoing lung structural impairment.




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