Of endostatin, whereas it reduced serum levels of VEGF. Like ticlopidine, both celecoxib and flurbiprofen substantially IL-17B Proteins Gene ID increased serum levels of endostatin, and increased the ratio of serum CXCL17 Proteins Gene ID endostatin to VEGF. However, the NO-releasing COX inhibitor, HCT-1026, elevated endostatin levels in serum, but also caused a parallel enhance in serum levels of VEGF. As a result, with HCT1026 treatment the ratio of serum endostatin to VEGF was unchanged from what’s observed in rats with ulcers that were not treated having a COX inhibitor. HCT-1026 did not interfere with ulcer healing, nor did it lead to the reduction of angiogenesis in the ulcer bed that was noticed with the other two COX inhibitors. Consistent with the alteration within the balance between pro- and antiangiogenic variables in serum, treatment with celecoxib or flurbiprofen altered the capacity on the serum to influence endoMa et al.thelial cell proliferation and apoptosis. Addition of rat serum to cultured HUVEC resulted in a rise in proliferation and also a decrease in apoptosis. Nonetheless, when the serum was from rats treated with celecoxib or flurbiprofen, the extent of proliferation was substantially decreased, however the extent of apoptosis was significantly increased. These in vitro effects are constant with an antiangiogenic impact from the serum, that is in turn constant together with the detrimental impact on ulcer healing. The fact that the reduction of HUVEC proliferation and improve in apoptosis was totally blocked by an antiendostatin antibody strongly suggests that the increases in serum endostatin levels elicited by treatment with flurbiprofen or celecoxib could have accounted for the delay in ulcer healing in rats treated with those drugs. Endostatin has been shown to inhibit endothelial cell proliferation (34) and migration (35), but to promote endothelial apoptosis (36). Although endostatin seems to become the key factor mediating modifications in HUVEC proliferation and apoptosis in response to exposure to serum from rats treated with flurbiprofen or celecoxib, the significant differences between the effects of HCT-1026 and these from the other COX inhibitors was observed with all the serum VEGF levels. All three from the COX inhibitors elevated serum endostatin, but only HCT-1026 substantially elevated serum VEGF. Along with the platelet, VEGF is produced by endothelial and vascular smooth muscle cells. The synthesis of VEGF by these cells has been shown1. Folkman, J., Szabo, S., Stovroff, M., McNeil, N., Li, W. Shing, Y. (1991) Ann. Surg. 241, 41425. 2. Schmassmann, A., Tarnawski, A., Peskar, B. M., Varga, L., Flogerzi, B. Halter, F. (1995) Am. J. Physiol. 268, G276 285. three. Tarnawski, A. Halter, F. (1995) J. Clin. Gastroenterol. 21, S93 97. 4. Schmassmann, A., Stettler, C., Poulsom, R., Tarasova, N., Hirschi, C., Flogerzi, B., Matsumoto, K., Nakamura, T. Halter, F. (1997) Gastroenterology 113, 1858872. 5. Szabo, S., Khomenko, T., Gombos, Z., Deng, X. M., Jadus, M. R. Yoshida, M. (2000) Aliment. Pharmacol. Ther. 14, Suppl. 1, 333. 6. Ma, L., Elliott, S. N., Cirino, G., Buret, A., Ignarro, L. J. Wallace, J. L. (2001) Proc. Natl. Acad. Sci. USA 98, 6470475. 7. Nagashima, M., Asano, G. Yoshino, S. (2002) J. Rheumatol. 27, 2339342. 8. Bombardier, C., Laine, L., Reicin, A., Shapiro, D., Burgos-Vargas, R., Davis, B., Day, R., Ferraz, M. B., Hawkey, C. J., Hochberg, M. C., et al. (2000) N. Engl. J. Med. 343, 1520528. 9. Mizuno, H., Sakamoto, C., Matsuda, K., Wada, K., Uchida, T., Noguchi, H., Akam.