Roles of pro-angiogenic and anti-angiogenic factors as well as matrix metalloproteinases in healing of NSAID-induced small intestinal ulcers in rats

Aims: We examined changes in the expression of a pro-angiogenic factor, vascular endothelial growth factor (VEGF), and an anti-angiogenic factor, endostatin, as well as matrix metalloproteinase (MMP)-2 and MMP-9 in the rat small intestine after administration of indomethacin and investigated the roles of these factors in the healing of indomethacin-induced small intestinal ulcers. Main methods: Male SD rats were given indomethacin (10 mg/kg) p.o. and euthanized at various time points (3-24 h and 2-7 days) after the administration. To impair the healing of these lesions, low-dose of indomethacin (2 mg/kg) was given p.o. once daily for 6 days starting 1 day after ulceration. Levels of VEGF, endostatin, MMP-2 and MMP-9 were determined by Western blotting. Key findings: The expression of both VEGF and endostatin was upregulated after the ulceration. Repeated administration of low-dose indomethacin impaired the ulcer healing with a decrease of VEGF expression and a further increase of endostatin expression, resulting in a marked decrease in the ratio of VEGF/endostatin expression. The levels of MMP-2 and MMP-9 were both significantly increased after the ulceration, but these responses were suppressed by the repeated indomethacin treatment. The healing of these ulcers was significantly delayed by the repeated administration of MMP inhibitors such as ARP-101 and SB-3CT. Significance: The results confirm the importance of the balance between pro-angiogenic and anti-angiogenic activities in the healing of indomethacin-induced small intestinal damage and further suggest that the increased expression of MMP-2 and MMP-9 is another important factor for ulcer healing in the small intestine. (c) 2013 Elsevier Inc. All rights reserved.