Background: 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.
Methods:
The CD4 รพ CD45RB high 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 VEGF 164 aptamer (Macugen), adenoviral VEGF 164 , and the VEGF Trap were used to evaluate pathological importance.
Results: 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 VEGF 164 using a highly selective RNA aptamer significantly attenuated CD4 รพ CD45RB high T-cell-dependent experimental colitis by reducing pathological angiogenesis and inflammatory pathology. Conversely, broadspectrum VEGF inhibition with VEGF Trap did not attenuate disease, nor did adenoviral VEGF 164 overexpression significantly alter colitis pathology.
Conclusions: VEGF 164 is actively produced by multiple cell types during T-cell-mediated colitis. Importantly, specific inhibition of the VEGF 164 isoform during T-cell-mediated colitis dose-dependently attenuated disease progression, while broadscale inhibition of all VEGF-A isoforms was not therapeutically beneficial.