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1 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
2 Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
* To whom correspondence should be addressed. E-mail: tim.lecras{at}CCHMC.ORG.
To determine whether increased levels of VEGF disrupt postnatal lung formation or function, conditional transgenic mice in which VEGF164 expression was enhanced in respiratory epithelial cells, were produced. VEGF expression was induced in the lungs of VEGF transgenic pups with doxycycline (Dox) from postnatal day 1 through 2 weeks and 6 weeks of age. VEGF levels were higher in bronchiolar alveolar lavage fluid (BALF) and lung homogenates of VEGF transgenic mice compared to endogenous VEGF levels in controls. Neonatal mortality was increased by 50% in VEGF transgenic mice. Total protein content in BALF was elevated in VEGF transgenic mice. SP-B protein expression was unaltered in VEGF transgenic mice. While postnatal alveolar and vascular development were not disrupted by VEGF expression, VEGF transgenic mice developed pulmonary hemorrhage, alveolar remodeling, and macrophage accumulation as early as 2 weeks of age. Electron microscopy demonstrated abnormal alveolar capillary endothelium in the VEGF transgenic mice. In many locations, the endothelium was discontinuous with segments of attenuated endothelial cells. Large numbers of hemosiderin-laden macrophages and varying degrees of emphysema were observed in adult VEGF transgenic mice. Overexpression of VEGF in the neonatal lung increased infant mortality, and caused pulmonary hemorrhage, hemosiderosis, alveolar remodeling, and inflammation.
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