Vascular approach to gastroduodenal ulceration: new studies with endothelins and VEGF.
Endothelins (ET) and VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) are products mainly of endothelial cells, which are also regulated via autocrine and paracrine pathways by these peptides. As a follow-up to our focus on vascular factors in ulcer pathogenesis and healing, we review here our recent studies with ET-1 and VEGF/VPF in animal models and human subjects. Our new results demonstrated a rapid and time-dependent release of ET-1 into the systemic circulation after intragastric administration of ethanol or HCI in rats, and ethanol in humans. The ET-1 release preceded the development of hemorrhagic erosions in both species and might be used as a diagnostic tool to noninvasively quantify acute gastric mucosal lesions. The development of solitary duodenal ulcers in the rat was preceded only by an organ- (involving only the duodenum and not the stomach) and molecule-specific (induced only by cysteamine and not by the nonulcerogenic analog ethanolamine) rapid local release of ET-1. The severity of cysteamine-induced duodenal ulcers was dose-dependently decreased by pretreatment 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 stimulated 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.
Szabo
S
S
Department of Pathology, University of California, Irvine, USA.
Vincze
A
A
Sandor
Z
Z
Jadus
M
M
Gombos
Z
Z
Pedram
A
A
Levin
E
E
Hagar
J
J
Iaquinto
G
G
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000378:metabolism*; D016232:Endothelins / Q000378:metabolism*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D010437:Peptic Ulcer / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016232:Endothelins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors