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Cyclooxygenase-2-regulated vascular endothelial growth factor release in gastric fibroblasts

¹Fifth Department of Internal Medicine, Tokyo Medical University, Ibaraki-Ken 300-0385; and ²Third Department of Internal Medicine, Nippon Medical School, Tokyo 113-8603, Japan

Submitted 29 December 2003 ; accepted in final form 22 March 2004

VEGF is a highly specific stimulator of endothelial cells and may play an important role in angiogenesis in the process of tissue regeneration. We previously showed that cyclooxygenase-2 (COX-2) expressed in mesenchymal cells of the ulcer bed is involved in the ulcer repair process. To clarify the role of COX-2 in angiogenesis during gastric ulcer healing, we investigated the relation between COX-2 expression and VEGF production in human gastric fibroblasts in vivo and in vitro. Gastric fibroblasts were cultured in RPMI 1640 with and without IL-1 or IL-1 in the presence or absence of NS-398, a selective COX-2 inhibitor. Supernatant VEGF and PGE₂ concentrations were measured by enzyme-linked immunosorbent assay. COX-2 expression in fibroblasts was determined by Western blot analysis. VEGF and COX-2 expression in surgical resections of human gastric ulcer tissue was examined immunohistochemically. IL-1 dose dependently enhanced VEGF release in cultured gastric fibroblasts after a 24-h stimulation. IL-1 also stimulated PGE₂ production in gastric fibroblasts via COX-2 induction. NS-398 significantly suppressed VEGF and PGE₂ release from IL-1-stimulated gastric fibroblasts; concurrent addition of PGE₂ restored NS-398-inhibited VEGF release. COX-2 and VEGF immunoreactivity were colocalized in fibroblast-like cells in the ulcer bed of gastric tissues. These results suggest that COX-2 plays a key role in VEGF production in gastric fibroblasts stimulated by IL-1 in vitro and that angiogenesis induced by the COX-2-VEGF pathway might be involved in gastric ulcer healing.

prostaglandin E₂; gastric ulcer; angiogenesis; repair process

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