Vascular endothelial growth factor receptor 2 blockade disrupts postnatal lung development.
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 1 wk of age, mice treated with DC101 on Days 2 and 4 of life had significantly larger mean alveolar diameters consistent with impaired alveolization. By 2 wk of age, however, perinatally treated DC101 mice had normal-appearing alveolar structure. Mice exposed to perinatal hyperoxia (O(2)) also had larger mean alveolar diameters at 1 wk of age, but unlike DC101-treated mice, their mitotic index was decreased at 1 wk of age and they had persistent alveolar enlargement beyond the first 2 wk of life. The O(2)-treated lung also had an increase in caspase 3 at 1 wk of age and significantly greater expression of nitrotyrosine at 2 wk 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.
McGrath-Morrow
Sharon A
SA
Department of Pediatric Pulmonary, Johns Hopkins Hospital, Park 316 N. Wolfe Street, Baltimore, MD 21287-2533, USA. smorrow@jhmi.edu
Cho
Cecilia
C
Cho
Chung
C
Zhen
Lijie
L
Hicklin
Daniel J
DJ
Tuder
Rubin M
RM
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000378:metabolism*; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008168:Lung / Q000033:anatomy & histology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D000906:Antibodies; C002744:3-nitrotyrosine; D014443:Tyrosine; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D010100:Oxygen