In
ulcerative colitis (UC), an increased expression of
vascular endothelial growth factor (
VEGF) correlates with disease activity, but a causal relationship is unknown. We tested the hypothesis that
VEGF plays a mechanistic role in the pathogenesis of experimental UC and that
VEGF neutralization may exert
therapeutic effect. UC was induced in Sprague-Dawley rats by 6%
iodoacetamide given intracolonically. Neutralizing anti-
VEGF antibody (50 microg/rat), nonspecific
IgG, or saline (0.1 ml/rat) was injected intramuscularly on the 3rd and 5th days after
iodoacetamide enema. Rats were euthanized on the 7th day. We examined the extent of macroscopic, histologic, and clinical features of
colitis and colonic vascular permeability. Colonic
VEGF mRNA and
protein expressions increased as early as 0.5 h after
iodoacetamide enema and remained elevated in the active phase of
colitis. Treatment with anti-
VEGF antibody markedly improved the clinical and morphologic features of UC. Colonic lesion area was significantly reduced from 370 +/- 140 or 311 +/- 170 mm(2) in saline- or
IgG-treated groups to 122 +/- 57 mm(2) in the anti-
VEGF-group (p < 0.05). Increased colonic vascular permeability was decreased by the anti-
VEGF antibody (p < 0.05) and the Src inhibitor PP1 [pyrazolopyrimidine, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-
pyrimidine] (p < 0.01). The number of acute and chronic inflammatory cells in the lesion area was significantly reduced in anti-
VEGF-treated rats. In the anti-
VEGF-treated group, mucosal levels of
VEGF,
platelet-derived growth factor, and
basic fibroblast growth factor were also reduced.
IN CONCLUSION: 1) Neutralizing anti-
VEGF antibody significantly ameliorates experimental UC in rats in part by reducing excessive vascular permeability and decreasing inflammatory cells infiltration; and 2)
VEGF seems to mediate increased colonic vascular permeability in experimental UC via the Src-dependent mechanism.