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Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung

Abstract

Exaggerated levels of VEGF (vascular endothelial growth factor) are present in persons with asthma, but the role(s) of VEGF in normal and asthmatic lungs has not been defined. We generated lung-targeted VEGF165 transgenic mice and evaluated the role of VEGF in T-helper type 2 cell (TH2)-mediated inflammation. In these mice, VEGF induced, through IL-13–dependent and –independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia and airway hyper-responsiveness. VEGF also enhanced respiratory antigen sensitization and TH2 inflammation and increased the number of activated DC2 dendritic cells. In antigen-induced inflammation, VEGF was produced by epithelial cells and preferentially by TH2 versus TH1 cells. In this setting, it had a critical role in TH2 inflammation, cytokine production and physiologic dysregulation. Thus, VEGF is a mediator of vascular and extravascular remodeling and inflammation that enhances antigen sensitization and is crucial in adaptive TH2 inflammation. VEGF regulation may be therapeutic in asthma and other TH2 disorders.

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Figure 1: Consequences of transgenic VEGF expression.
Figure 2: Structural alterations in transgenic (TG) mice.
Figure 3: Role of IL-13 in the VEGF phenotype.
Figure 4: Immune effects of VEGF.
Figure 5: VEGF in TH2 inflammation.
Figure 6: Reversibility of VEGF effects.

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Acknowledgements

The authors thank K. Bertier and S. Ardito for their excellent secretarial assistance, A. Haskell for performing the electron microscopy and E. Ator for help with lectin staining. The authors also thank the other investigators and institutions that provided the reagents that were used. This research was supported in part by NIH grants HL-64642, HL-61904, HL-56389 and HL-78744 (J.A.E.) and HL-24136 and HL-59157 (D.M.) from the NHLBI of the National Institutes of Health USA.

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Correspondence to Jack A Elias.

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Supplementary information

Supplementary Fig. 1

Localization of Gob-5 mRNA expression by RNA in situ hybridization (PDF 87 kb)

Supplementary Fig. 2

Localization of VEGF expression in epithelial cells of OVA sensitized and challenged mice (PDF 79 kb)

Supplementary Fig. 3

Role of VEGF in Th2 inflammation (PDF 238 kb)

Supplementary Fig. 4

VEGF expression of Th1 and Th2 cells in the absence of antigen presenting cells (APC) (PDF 44 kb)

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Lee, C., Link, H., Baluk, P. et al. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med 10, 1095–1103 (2004). https://doi.org/10.1038/nm1105

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