Inhibition of VEGF receptors causes lung cell apoptosis and emphysema
Yasunori Kasahara, Rubin M. Tuder, Laimute Taraseviciene-Stewart, Timothy D. Le Cras, Steven Abman, Peter K. Hirth, Johannes Waltenberger, Norbert F. Voelkel
Yasunori Kasahara, Rubin M. Tuder, Laimute Taraseviciene-Stewart, Timothy D. Le Cras, Steven Abman, Peter K. Hirth, Johannes Waltenberger, Norbert F. Voelkel
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Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

Abstract

Pulmonary emphysema, a significant global health problem, is characterized by a loss of alveolar structures. Because VEGF is a trophic factor required for the survival of endothelial cells and is abundantly expressed in the lung, we hypothesized that chronic blockade of VEGF receptors could induce alveolar cell apoptosis and emphysema. Chronic treatment of rats with the VEGF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema. The VEGF receptor inhibitor SU5416 induced alveolar septal cell apoptosis but did not inhibit lung cell proliferation. Viewed by angiography, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fibrosis. SU5416 treatment led to a decrease in lung expression of VEGF receptor 2 (VEGFR-2), phosphorylated VEGFR-2, and Akt-1 in the complex with VEGFR-2. Treatment with the caspase inhibitor Z-Asp-CH2-DCB prevented SU5416-induced septal cell apoptosis and emphysema development. These findings suggest that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema.

Authors

Yasunori Kasahara, Rubin M. Tuder, Laimute Taraseviciene-Stewart, Timothy D. Le Cras, Steven Abman, Peter K. Hirth, Johannes Waltenberger, Norbert F. Voelkel

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(a) Expression of VEGFR-2 in lungs of rats treated with vehicle (control...
(a) Expression of VEGFR-2 in lungs of rats treated with vehicle (control); SU5416 for 3, 7, or 21 days; or SU5416 + Z-Asp-CH2-DCB for 21 days. Each data point represents the average of expression in two lungs per experimental group. The bands were quantitated by densitometry, followed by normalization for loading and determination of protein integrity using β-actin expression. (b) Assessment of phosphorylated (active) VEGFR-2 in lungs of rats treated with vehicle (control); SU5416 for 3, 7, or 21 days; or SU5416 + Z-Asp-CH2-DCB for 21 days, by immunoprecipitation with anti–VEGFR-2 antibody and Western blot for VEGFR-2 and its phosphorylated form. Each data point represents the average of expression in two lungs per experimental group, and the data are expressed as the ratio of phosphorylated VEGFR-2 to nonphosphorylated VEGFR-2. (c) Assessment of Akt-1 in the complex with VEGFR-2 performed by immunoprecipitation with anti–VEGFR-2 antibody, and Western blot for VEGFR-2 and Akt-1. Data are expressed as the ratio of Akt-1 to VEGFR-2. (d) Assessment of PI3 kinase in the complex with VEGFR-2 performed by immunoprecipitation with anti-VEGFR-2 antibody, and Western blot for VEGFR-2 and PI3 kinase. Data are expressed as the ratio of PI3 kinase to VEGFR-2.