Supported by NIH grant P01 DK043785-18 Project 4, and Animal models and Histopathology cores.
VEGF164 isoform specific regulation of T-cell-dependent experimental colitis in mice†
Article first published online: 9 NOV 2010
Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 17, Issue 7, pages 1501–1512, July 2011
How to Cite
Chidlow, J. H., Glawe, J. D., Pattillo, C. B., Pardue, S., Zhang, S. and Kevil, C. G. (2011), VEGF164 isoform specific regulation of T-cell-dependent experimental colitis in mice. Inflamm Bowel Dis, 17: 1501–1512. doi: 10.1002/ibd.21525
- Issue published online: 14 JUN 2011
- Article first published online: 9 NOV 2010
- Manuscript Accepted: 20 SEP 2010
- Manuscript Received: 14 SEP 2010
- T cell
Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC), two widespread diseases of unknown, multifactorial etiology. Colitis pathology involves a pathological angiogenic response where increases in vascular density participate in colitis histopathology. Vascular endothelial growth factor-A (VEGF-A) is a potent angiogenesis stimulator known to be involved in pathological angiogenesis in several diseases including colitis. However, the pathogenic importance of specific VEGF-A isoforms during T-cell-mediated experimental colitis remains largely unknown.
The CD4+CD45RBhigh T-cell transfer model of experimental colitis was used for these studies. The VEGF lac-Z transgenic reporter mouse was used to examine specific cellular sources of VEGF-A production. The VEGF164 aptamer (Macugen), adenoviral VEGF164, and the VEGF Trap were used to evaluate pathological importance.
VEGF lac-Z reporter mice experiments showed that both infiltrating T cells and local tissue cells produce VEGF-A in the colon during disease. Inhibition of VEGF164 using a highly selective RNA aptamer significantly attenuated CD4+CD45RBhigh T-cell-dependent experimental colitis by reducing pathological angiogenesis and inflammatory pathology. Conversely, broad-spectrum VEGF inhibition with VEGF Trap did not attenuate disease, nor did adenoviral VEGF164 overexpression significantly alter colitis pathology.
VEGF164 is actively produced by multiple cell types during T-cell-mediated colitis. Importantly, specific inhibition of the VEGF164 isoform during T-cell-mediated colitis dose-dependently attenuated disease progression, while broad-scale inhibition of all VEGF-A isoforms was not therapeutically beneficial. (Inflamm Bowel Dis 2010)