Submitted on September 6, 2006
Accepted on October 17, 2006
A novel role of Fibroblast Growth Factor-2 and Pentosan Polysulphate in the pathogenesis of intestinal bleeding in mice
Marina Jerebtsova1, Edward Wong2, Ronald Przygodzki3, Pingtao Tang4, and Patricio E. Ray5*
1 Department of Pediatrics, The George Washington University, Children's Research Institute, Washington , District of Columbia, United States
2 Department of Pediatrics, The George Washington University, Division of Hematology, Children's National Medical Center, Washington , District of Columbia, United States
3 Departments of Pediatrics and Pathology, The George Washington University, Division of Pathology, Children's National Medical Center, Washington , District of Columbia, United States
4 Children's Research Institute, Children's National Medical Center, Washington , District of Columbia, United States
5 Department of Pediatrics, The George Washington University, Children's Research Institute, Division of Nephrology, Children's National Medical Center, Washington, District of Columbia, United States
* To whom correspondence should be addressed. E-mail: pray{at}cnmc.org.
Pentosan polysulphate (PPS) is a heparin-like polysaccharide that can affect the binding interactions of FGF-2 with its receptors. Patients with angiogenic tumors frequently show high levels of Fibroblast Growth Factor (FGF-2) in the circulation. Since FGF-2 is a heparin binding growth factor, PPS has been used successfully to block its angiogenic activity in these patients. However, because of its heparin-like activity, the major toxic effect related to the systemic use of PPS is the development of bleeding disorders. The role that circulating FGF-2 plays in the pathogenesis of these bleeding disorders is not clearly understood. Here, we hypothesized that FGF-2 might play a physiological role in the pathogenesis of intestinal bleeding induced by PPS. This hypothesis is supported by previous studies showing that PPS is accumulated in the intestine; and that circulating FGF-2 specifically binds to and modulates the angiogenic activity of intestinal submucosal endothelial cells. We used recombinant adenoviral vectors carrying a secreted form of FGF-2 and Lac-Z control vectors to determine whether high levels of circulating FGF-2 facilitate the development of intestinal bleeding disorders in FVB/N and C57BL/6J mice treated with PPS. We found that PPS, acting together with FGF-2, induced structural changes in intestinal vessels leading to the development of lethal intestinal hemorrhages. These findings might have wider clinical implications for the systemic use of PPS and other heparinoids in the treatment of patients with angiogenic diseases associated with high levels of circulating FGF-2.
