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-overexpressing mice is
associated with decreased VEGF gene expression
1 Research Institute for Disease of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 Japan; 2 Department of Medicine, National Jewish Medical and Research Center, Denver 80206; 3 Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262; 4 Pulmonary Biology, Children's Hospital Medical Center of Cincinnati, Cincinnati, Ohio 45229; and 5 Department of Medicine, Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Science Center, Denver, Colorado 80262
Tumor necrosis factor-
(TNF-) transgenic mice have previously been found to have
characteristics consistent with emphysema and severe pulmonary
hypertension. Lungs demonstrated alveolar enlargement as well as
interstitial thickening due to chronic inflammation and perivascular
fibrosis. In the present report, we sought to determine potential
mechanisms leading to development of pulmonary hypertension in TNF-
transgenic mice. To determine whether sustained vasoconstriction was an
important component of this pulmonary hypertension, nitric oxide was
administered and hemodynamics were measured. Nitric oxide (25 ppm)
failed to normalize right ventricular pressure in transgene-positive
mice, suggesting that the pulmonary hypertension was not due to
sustained vasoconstriction. Structural analysis of the pulmonary
arteries found adventitial thickening and a trend toward medial
hypertrophy in pulmonary arteries of transgene-positive mice,
suggesting that vascular remodeling had occurred. Echocardiographic
measurement of the percent fractional shortening of the left ventricle
as a measurement of ventricular function in vivo revealed that left ventricular dysfunction was not contributing to pulmonary hypertension. We examined expression of genes known to be important in regulation of
vascular tone and structure. Messenger RNA expression of vascular endothelial growth factor and its receptor flk-1 was reduced compared with transgene-negative littermates at all ages. Endothelial and inducible nitric oxide synthase mRNA levels were similar in both groups. Endothelin-1 mRNA was also decreased in TNF- transgenic mice. Interestingly, female transgenic mice had decreased survival rate
compared with male transgenic mice. We conclude that chronic overexpression of TNF- is associated with decreased vascular endothelial growth factor and flk-1 gene expression, pulmonary vascular
remodeling, and severe pulmonary hypertension, although the precise
mechanism is unknown.
tumor necrosis factor-; vascular endothelial growth factor; nitric oxide; endothelin
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