VASCULAR APPROACH TO GASTRODUODENAL ULCERATION - NEW STUDIES WITH ENDOTHELINS AND VEGF

Endothelins (ET) and VEGF/VPF (vascular endothelial growth factor/vasc ular permeability factor) are products mainly of endothelial cells, wh ich are also regulated via autocrine and paracrine pathways by these p eptides. As a follow-up to our focus on vascular factors in ulcer path ogenesis and healing, we review here our recent studies with ET-1 and VEGF/VPF in animal models and human subjects. Our new results demonstr ated a rapid and time-dependent release of ET-1 into the systemic circ ulation after intragastric administration of ethanol or HCl in rats, a nd ethanol in humans. The ET-1 release preceded the development of hem orrhagic erosions in both species and might be used as a diagnostic to ol to noninvasively quantify acute gastric mucosal lesions. The develo pment of solitary duodenal ulcers in the rat was preceded only by an o rgan- (involving only the duodenum and not the stomach) and molecule-s pecific (induced only by cysteamine and not by the nonulcerogenic anal og ethanolamine) rapid local release of ET-1. The severity of cysteami ne-induced duodenal ulcers was dose-dependently decreased by pretreatm ent with ET-1 antibodies or antagonist bosentan. A single intragastric dose of VEGF/VPF resulted in gastroprotection against ethanol, while daily intragastric treatment with the peptide for three weeks stimulat ed angiogenesis in the base of cysteamine-induced duodenal ulcers and accelerated ulcer healing. Thus, modulation of vascular factors seems to be sufficient for both acute gastroprotection and chronic duodenal ulcer healing.