Gastrointestinal (GI)
ulcers are essentially internal
wounds that resist normal healing processes. Since their pathogenesis is poorly understood, and the etiologic (e.g., gastric acid,
aspirin-like drugs, stress) and aggravating factors (e.g., H. pylori) are not well characterized, the remaining therapeutic option is to accelerate healing. Superficial mucosal lesions, i.e., erosions usually heal by epithelial regeneration and restitution, but when
ulcers involve the muscularis propria, smooth muscle cells do not divide/regenerate. These deep lesions are filled by granulation tissue, i.e., angiogenesis followed by proliferation of connective tissue fibroblasts that deposit
collagen over which adjacent surviving and dividing epithelial cells migrate to complete the healing. Our laboratory was the first to postulate that stimulation of angiogenesis alone might be sufficient to accelerate
ulcer healing in the GI tract. Indeed, daily treatment of rats with bFGF, PDGF or
VEGF markedly improved the healing of
cysteamine-induced chronic
duodenal ulcers, without any reduction in gastric acid secretion. These results were reproduced by a single dose of gene therapy by adenoviral vectors encoding PDGF or
VEGF genes. The molar potency of angiogenic
growth factors was 2-7 million times better than the antiulcerogenic effect of antisecretory H2 antagonists. Since histologically & pathologically
gastroduodenal ulcers look similar to
ulcers in the lower GI tract, we also predicted that the healing of experimental
ulcerative colitis might be also improved by these angiogenic
growth factors. Rectal
enemas containing bFGF or PDGF indeed accelerated the healing of chemically induced
ulcerative colitis in rats.
VEGF, also known as VPF (
vascular permeability factor), however, had no effect or slightly aggravated the colonic lesions. Injection of anti-
VEGF neutralizing antibodies, however, counteracted the increased vascular permeability in the early stages of experimental
ulcerative colitis and subsequently decreased the number of inflammatory cells in colonic
ulcers in rats, resulting in significantly improved healing in the lower GI tract lesions. Thus, the three angiogenic
growth factors tested exerted beneficial effect on
gastroduodenal ulcers, and rectal
enemas with bFGF or PDGF also accelerated the healing of experimental
ulcerative colitis. Surprisingly, we achieved the latter effect with anti-
VEGF antibodies, most likely because of the pro-inflammatory actions of
VEGF in the pathogenesis of
ulcerative colitis.